WO2014064149A1 - 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitors - Google Patents
4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitors Download PDFInfo
- Publication number
- WO2014064149A1 WO2014064149A1 PCT/EP2013/072165 EP2013072165W WO2014064149A1 WO 2014064149 A1 WO2014064149 A1 WO 2014064149A1 EP 2013072165 W EP2013072165 W EP 2013072165W WO 2014064149 A1 WO2014064149 A1 WO 2014064149A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- dihydro
- formula
- oxo
- isoindole
- carboxylic acid
- Prior art date
Links
- 239000003112 inhibitor Substances 0.000 title description 11
- 101100407073 Caenorhabditis elegans parp-1 gene Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 235
- 238000000034 method Methods 0.000 claims abstract description 55
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 35
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 16
- 201000011510 cancer Diseases 0.000 claims abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 9
- 206010061218 Inflammation Diseases 0.000 claims abstract description 8
- 208000001738 Nervous System Trauma Diseases 0.000 claims abstract description 8
- 230000004054 inflammatory process Effects 0.000 claims abstract description 8
- 208000028412 nervous system injury Diseases 0.000 claims abstract description 8
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 7
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 claims abstract description 7
- 210000003169 central nervous system Anatomy 0.000 claims abstract description 4
- -1 [1-(4,4-dimethyl-cyclohexyl)-piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1 H-isoindole-4-carboxylic acid amide Chemical compound 0.000 claims description 57
- 125000003118 aryl group Chemical group 0.000 claims description 36
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 229940100198 alkylating agent Drugs 0.000 claims description 13
- 239000002168 alkylating agent Substances 0.000 claims description 13
- 108090000623 proteins and genes Proteins 0.000 claims description 13
- 230000008569 process Effects 0.000 claims description 12
- 210000004027 cell Anatomy 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 102000004169 proteins and genes Human genes 0.000 claims description 10
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical group O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 8
- 229940127089 cytotoxic agent Drugs 0.000 claims description 8
- 229910052731 fluorine Chemical group 0.000 claims description 8
- 239000011737 fluorine Chemical group 0.000 claims description 8
- 229960004964 temozolomide Drugs 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 102000015087 Poly (ADP-Ribose) Polymerase-1 Human genes 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 210000000481 breast Anatomy 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 238000006268 reductive amination reaction Methods 0.000 claims description 5
- QBKPYKWJSWOHNY-UHFFFAOYSA-N 2-(1-cyclohexylpiperidin-4-yl)-3-oxo-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1C(CC1)CCN1C1CCCCC1 QBKPYKWJSWOHNY-UHFFFAOYSA-N 0.000 claims description 4
- XEVOIPORGFHFTR-UHFFFAOYSA-N 2-[1-(furan-2-ylmethyl)piperidin-4-yl]-3-oxo-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1C(CC1)CCN1CC1=CC=CO1 XEVOIPORGFHFTR-UHFFFAOYSA-N 0.000 claims description 4
- JGWQDYTVDJMRNI-UHFFFAOYSA-N 3-oxo-2-(3-phenylpropyl)-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1CCCC1=CC=CC=C1 JGWQDYTVDJMRNI-UHFFFAOYSA-N 0.000 claims description 4
- RBNSMVGFGNNHLH-UHFFFAOYSA-N 3-oxo-2-[1-(thiophen-3-ylmethyl)piperidin-4-yl]-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1C(CC1)CCN1CC=1C=CSC=1 RBNSMVGFGNNHLH-UHFFFAOYSA-N 0.000 claims description 4
- YYMORWAQDHOTFE-UHFFFAOYSA-N 6-fluoro-2-(3-morpholin-4-ylpropyl)-3-oxo-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC(F)=CC=2CN1CCCN1CCOCC1 YYMORWAQDHOTFE-UHFFFAOYSA-N 0.000 claims description 4
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 4
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 4
- 230000002152 alkylating effect Effects 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 238000011319 anticancer therapy Methods 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- 201000005787 hematologic cancer Diseases 0.000 claims description 4
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 210000001685 thyroid gland Anatomy 0.000 claims description 4
- NBKCBJOAWBBQEW-UHFFFAOYSA-N 2-(1-benzylpiperidin-4-yl)-3-oxo-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1C(CC1)CCN1CC1=CC=CC=C1 NBKCBJOAWBBQEW-UHFFFAOYSA-N 0.000 claims description 3
- FKYQTFXJWMLOJE-UHFFFAOYSA-N 2-(1-cyclohexylpiperidin-4-yl)-6-fluoro-3-oxo-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC(F)=CC=2CN1C(CC1)CCN1C1CCCCC1 FKYQTFXJWMLOJE-UHFFFAOYSA-N 0.000 claims description 3
- SDTLVPAVHMUAEM-UHFFFAOYSA-N 2-(2-morpholin-4-ylethyl)-3-oxo-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1CCN1CCOCC1 SDTLVPAVHMUAEM-UHFFFAOYSA-N 0.000 claims description 3
- FGRNZZFSZOJDGC-UHFFFAOYSA-N 2-(3-morpholin-4-ylpropyl)-3-oxo-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1CCCN1CCOCC1 FGRNZZFSZOJDGC-UHFFFAOYSA-N 0.000 claims description 3
- FSXCZROERMGUME-UHFFFAOYSA-N 2-[1-(cyclopropylmethyl)piperidin-4-yl]-3-oxo-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1C(CC1)CCN1CC1CC1 FSXCZROERMGUME-UHFFFAOYSA-N 0.000 claims description 3
- HAPBLGPUQRBOCG-UHFFFAOYSA-N 2-[1-(furan-3-ylmethyl)piperidin-4-yl]-3-oxo-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1C(CC1)CCN1CC=1C=COC=1 HAPBLGPUQRBOCG-UHFFFAOYSA-N 0.000 claims description 3
- JDUWWYRZYIZTIV-UHFFFAOYSA-N 2-[1-(oxan-4-yl)piperidin-4-yl]-3-oxo-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1C(CC1)CCN1C1CCOCC1 JDUWWYRZYIZTIV-UHFFFAOYSA-N 0.000 claims description 3
- UREAUZAZNZXBOS-UHFFFAOYSA-N 2-[2-(3,4-dihydro-1h-isoquinolin-2-yl)ethyl]-3-oxo-1h-isoindole-4-carboxamide Chemical compound C1CC2=CC=CC=C2CN1CCN1CC(C=CC=C2C(=O)N)=C2C1=O UREAUZAZNZXBOS-UHFFFAOYSA-N 0.000 claims description 3
- WGTJWDKKJAQXMI-UHFFFAOYSA-N 2-[2-(3,4-dihydro-2h-quinolin-1-yl)ethyl]-3-oxo-1h-isoindole-4-carboxamide Chemical compound C1CCC2=CC=CC=C2N1CCN1CC(C=CC=C2C(=O)N)=C2C1=O WGTJWDKKJAQXMI-UHFFFAOYSA-N 0.000 claims description 3
- CPZFBGJDYPLHHM-UHFFFAOYSA-N 2-[3-(3,4-dihydro-1h-isoquinolin-2-yl)propyl]-3-oxo-1h-isoindole-4-carboxamide Chemical compound C1CC2=CC=CC=C2CN1CCCN1CC(C=CC=C2C(=O)N)=C2C1=O CPZFBGJDYPLHHM-UHFFFAOYSA-N 0.000 claims description 3
- BLEKTFVHUNKMKI-UHFFFAOYSA-N 2-[3-(3,4-dihydro-2h-quinolin-1-yl)propyl]-3-oxo-1h-isoindole-4-carboxamide Chemical compound C1CCC2=CC=CC=C2N1CCCN1CC(C=CC=C2C(=O)N)=C2C1=O BLEKTFVHUNKMKI-UHFFFAOYSA-N 0.000 claims description 3
- XURWTHPKVQLLQP-UHFFFAOYSA-N 2-[3-(4-benzylpiperidin-1-yl)propyl]-3-oxo-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1CCCN(CC1)CCC1CC1=CC=CC=C1 XURWTHPKVQLLQP-UHFFFAOYSA-N 0.000 claims description 3
- QWUJLDJJCCLSKH-UHFFFAOYSA-N 2-[3-(4-methylpiperazin-1-yl)propyl]-3-oxo-1h-isoindole-4-carboxamide Chemical compound C1CN(C)CCN1CCCN1C(=O)C2=C(C(N)=O)C=CC=C2C1 QWUJLDJJCCLSKH-UHFFFAOYSA-N 0.000 claims description 3
- BDTIOERZNDWXLC-UHFFFAOYSA-N 2-benzyl-3-oxo-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1CC1=CC=CC=C1 BDTIOERZNDWXLC-UHFFFAOYSA-N 0.000 claims description 3
- QPPAHKUVUUORLS-UHFFFAOYSA-N 3-oxo-1-(2-phenylethyl)-1,2-dihydroisoindole-4-carboxamide Chemical compound O=C1NC(C=2C=CC=C(C12)C(=O)N)CCC1=CC=CC=C1 QPPAHKUVUUORLS-UHFFFAOYSA-N 0.000 claims description 3
- VWJCDLNJKREQPG-UHFFFAOYSA-N 3-oxo-2-(2-piperidin-1-ylethyl)-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1CCN1CCCCC1 VWJCDLNJKREQPG-UHFFFAOYSA-N 0.000 claims description 3
- JDJQWPULECUFIA-UHFFFAOYSA-N 3-oxo-2-(2-pyridin-2-ylethyl)-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1CCC1=CC=CC=N1 JDJQWPULECUFIA-UHFFFAOYSA-N 0.000 claims description 3
- RRKFGRBPRSLJIT-UHFFFAOYSA-N 3-oxo-2-[1-(1h-pyrrol-2-ylmethyl)piperidin-4-yl]-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1C(CC1)CCN1CC1=CC=CN1 RRKFGRBPRSLJIT-UHFFFAOYSA-N 0.000 claims description 3
- CCGJVGSERDTSKY-UHFFFAOYSA-N 3-oxo-2-[1-(pyridin-2-ylmethyl)piperidin-4-yl]-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1C(CC1)CCN1CC1=CC=CC=N1 CCGJVGSERDTSKY-UHFFFAOYSA-N 0.000 claims description 3
- OVLKNUOJLKTKMD-UHFFFAOYSA-N 3-oxo-2-[1-(pyridin-3-ylmethyl)piperidin-4-yl]-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1C(CC1)CCN1CC1=CC=CN=C1 OVLKNUOJLKTKMD-UHFFFAOYSA-N 0.000 claims description 3
- VASLQBSSVPMGKR-UHFFFAOYSA-N 3-oxo-2-[1-(thiophen-2-ylmethyl)piperidin-4-yl]-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1C(CC1)CCN1CC1=CC=CS1 VASLQBSSVPMGKR-UHFFFAOYSA-N 0.000 claims description 3
- QUPVUNKXVXHSQT-UHFFFAOYSA-N 3-oxo-2-[3-(4-phenylpiperazin-1-yl)propyl]-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1CCCN(CC1)CCN1C1=CC=CC=C1 QUPVUNKXVXHSQT-UHFFFAOYSA-N 0.000 claims description 3
- 238000005698 Diels-Alder reaction Methods 0.000 claims description 3
- 206010025323 Lymphomas Diseases 0.000 claims description 3
- 230000001093 anti-cancer Effects 0.000 claims description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- LNTOCZQBEVKZCM-UHFFFAOYSA-N 2-[1-(4,4-dimethylcyclohexyl)piperidin-4-yl]-3-oxo-1h-isoindole-4-carboxamide Chemical compound C1CC(C)(C)CCC1N1CCC(N2C(C3=C(C(N)=O)C=CC=C3C2)=O)CC1 LNTOCZQBEVKZCM-UHFFFAOYSA-N 0.000 claims description 2
- VRBNZCUDGAWEMP-UHFFFAOYSA-N 2-[2-(1-benzylpiperidin-4-yl)ethyl]-3-oxo-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1CCC(CC1)CCN1CC1=CC=CC=C1 VRBNZCUDGAWEMP-UHFFFAOYSA-N 0.000 claims description 2
- QKSNNWPLGOKMHZ-UHFFFAOYSA-N 2-[3-(2,6-dimethylpiperidin-1-yl)propyl]-3-oxo-1h-isoindole-4-carboxamide Chemical compound CC1CCCC(C)N1CCCN1C(=O)C2=C(C(N)=O)C=CC=C2C1 QKSNNWPLGOKMHZ-UHFFFAOYSA-N 0.000 claims description 2
- AYCSKTNVOSIFIU-UHFFFAOYSA-N 3-oxo-2-(1-spiro[2.5]octan-6-ylpiperidin-4-yl)-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1C(CC1)CCN1C(CC1)CCC21CC2 AYCSKTNVOSIFIU-UHFFFAOYSA-N 0.000 claims description 2
- GKALQNMQWUAENE-UHFFFAOYSA-N 3-oxo-2-(3-piperidin-1-ylpropyl)-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1CCCN1CCCCC1 GKALQNMQWUAENE-UHFFFAOYSA-N 0.000 claims description 2
- IFYZHTOYLJQIFK-UHFFFAOYSA-N 3-oxo-2-[3-(4-piperidin-1-ylpiperidin-1-yl)propyl]-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1CCCN(CC1)CCC1N1CCCCC1 IFYZHTOYLJQIFK-UHFFFAOYSA-N 0.000 claims description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 2
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims description 2
- 206010003571 Astrocytoma Diseases 0.000 claims description 2
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 2
- 208000011691 Burkitt lymphomas Diseases 0.000 claims description 2
- 201000009030 Carcinoma Diseases 0.000 claims description 2
- 208000006168 Ewing Sarcoma Diseases 0.000 claims description 2
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 2
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 2
- 206010029260 Neuroblastoma Diseases 0.000 claims description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 2
- 201000010208 Seminoma Diseases 0.000 claims description 2
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 2
- 206010042971 T-cell lymphoma Diseases 0.000 claims description 2
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 2
- 201000006083 Xeroderma Pigmentosum Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 230000002862 amidating effect Effects 0.000 claims description 2
- 238000005899 aromatization reaction Methods 0.000 claims description 2
- 210000003679 cervix uteri Anatomy 0.000 claims description 2
- 238000009104 chemotherapy regimen Methods 0.000 claims description 2
- 210000001072 colon Anatomy 0.000 claims description 2
- 210000003238 esophagus Anatomy 0.000 claims description 2
- 230000003325 follicular Effects 0.000 claims description 2
- 210000000232 gallbladder Anatomy 0.000 claims description 2
- 238000000338 in vitro Methods 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 210000004072 lung Anatomy 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 208000007538 neurilemmoma Diseases 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- 210000001672 ovary Anatomy 0.000 claims description 2
- 210000000496 pancreas Anatomy 0.000 claims description 2
- 210000001428 peripheral nervous system Anatomy 0.000 claims description 2
- 210000002307 prostate Anatomy 0.000 claims description 2
- 230000004952 protein activity Effects 0.000 claims description 2
- 238000001959 radiotherapy Methods 0.000 claims description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 2
- 210000003491 skin Anatomy 0.000 claims description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 2
- 210000002784 stomach Anatomy 0.000 claims description 2
- 208000001608 teratocarcinoma Diseases 0.000 claims description 2
- 210000003932 urinary bladder Anatomy 0.000 claims description 2
- 102100023652 Poly [ADP-ribose] polymerase 2 Human genes 0.000 abstract description 15
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 6
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 abstract description 2
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 abstract description 2
- 101710144590 Poly [ADP-ribose] polymerase 2 Proteins 0.000 abstract 1
- 238000000132 electrospray ionisation Methods 0.000 description 105
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- 238000005160 1H NMR spectroscopy Methods 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 45
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 44
- 239000000243 solution Substances 0.000 description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 101001113483 Homo sapiens Poly [ADP-ribose] polymerase 1 Proteins 0.000 description 31
- MPBLVPMGVIUHFH-UHFFFAOYSA-N 77960-22-6 Chemical compound O=C1C2C(C(=O)O)C(C=C3)OC23CN1CCC1=CC=CC=C1 MPBLVPMGVIUHFH-UHFFFAOYSA-N 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- VJTKXHGFYZSICV-UHFFFAOYSA-N OC(=O)c1cccc2CN(CCN3CCc4ccccc4C3)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(CCN3CCc4ccccc4C3)C(=O)c12 VJTKXHGFYZSICV-UHFFFAOYSA-N 0.000 description 29
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- 239000002904 solvent Substances 0.000 description 28
- BBPSJVAZBMTEFN-UHFFFAOYSA-N 3-(3,4-dihydro-1H-isoquinolin-2-yl)-N-(furan-2-ylmethyl)propan-1-amine Chemical compound C1N(CCC2=CC=CC=C12)CCCNCC=1OC=CC1 BBPSJVAZBMTEFN-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 125000000623 heterocyclic group Chemical group 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 21
- 238000010992 reflux Methods 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 101001113440 Homo sapiens Poly [ADP-ribose] polymerase 2 Proteins 0.000 description 14
- 101710179684 Poly [ADP-ribose] polymerase Proteins 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 230000002829 reductive effect Effects 0.000 description 13
- VOFBSAUUUDKWGR-UHFFFAOYSA-N 2-bromo-4-fluoro-6-methylbenzoic acid Chemical compound CC1=CC(F)=CC(Br)=C1C(O)=O VOFBSAUUUDKWGR-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- AJLWZNNKJCBLHC-UHFFFAOYSA-N methyl 2-bromo-4-fluoro-6-methylbenzoate Chemical compound COC(=O)C1=C(C)C=C(F)C=C1Br AJLWZNNKJCBLHC-UHFFFAOYSA-N 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 11
- MQXDQEGOVMUOPA-UHFFFAOYSA-N 1-cyclohexylpiperidin-4-amine;hydrate;dihydrochloride Chemical compound O.Cl.Cl.C1CC(N)CCN1C1CCCCC1 MQXDQEGOVMUOPA-UHFFFAOYSA-N 0.000 description 10
- LMVWQDFSKGIBEL-UHFFFAOYSA-N 2-(1-cyclohexylpiperidin-4-yl)-6-fluoro-3-oxo-1H-isoindole-4-carbonitrile Chemical compound Fc1cc2CN(C3CCN(CC3)C3CCCCC3)C(=O)c2c(c1)C#N LMVWQDFSKGIBEL-UHFFFAOYSA-N 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- 235000011114 ammonium hydroxide Nutrition 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 239000003643 water by type Substances 0.000 description 10
- UZHCHLVKCNNMNF-UHFFFAOYSA-N 2-bromo-4-fluoro-6-methylbenzamide Chemical compound CC1=CC(F)=CC(Br)=C1C(N)=O UZHCHLVKCNNMNF-UHFFFAOYSA-N 0.000 description 9
- JHKAGGIPLGOTCY-UHFFFAOYSA-N 2-bromo-4-fluoro-6-methylbenzonitrile Chemical compound CC1=CC(F)=CC(Br)=C1C#N JHKAGGIPLGOTCY-UHFFFAOYSA-N 0.000 description 9
- KDXOONIQRUZGSY-UHFFFAOYSA-N 4-fluoro-2-methylbenzoic acid Chemical compound CC1=CC(F)=CC=C1C(O)=O KDXOONIQRUZGSY-UHFFFAOYSA-N 0.000 description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 9
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 238000007796 conventional method Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- KMHLGVTVACLEJE-UHFFFAOYSA-N 4-fluoro-2-methylaniline Chemical compound CC1=CC(F)=CC=C1N KMHLGVTVACLEJE-UHFFFAOYSA-N 0.000 description 8
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 8
- 239000002953 phosphate buffered saline Substances 0.000 description 8
- 235000011181 potassium carbonates Nutrition 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- 235000015424 sodium Nutrition 0.000 description 8
- 229910000029 sodium carbonate Inorganic materials 0.000 description 8
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 7
- 102100034935 Protein mono-ADP-ribosyltransferase PARP3 Human genes 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 235000011121 sodium hydroxide Nutrition 0.000 description 7
- AWDBHOZBRXWRKS-UHFFFAOYSA-N tetrapotassium;iron(6+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+6].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] AWDBHOZBRXWRKS-UHFFFAOYSA-N 0.000 description 7
- 238000011282 treatment Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- 239000012661 PARP inhibitor Substances 0.000 description 6
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 6
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 229910052796 boron Inorganic materials 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- LVGDEACFPFFUFB-UHFFFAOYSA-N methyl 2-cyano-4-fluoro-6-methylbenzoate Chemical compound COC(=O)C1=C(C)C=C(F)C=C1C#N LVGDEACFPFFUFB-UHFFFAOYSA-N 0.000 description 6
- 230000035772 mutation Effects 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 5
- 101710176890 Protein ADP-ribosyltransferase PARP3 Proteins 0.000 description 5
- 101710204718 Protein mono-ADP-ribosyltransferase PARP3 Proteins 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000010949 copper Substances 0.000 description 5
- 229910052802 copper Inorganic materials 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000012091 fetal bovine serum Substances 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 230000009466 transformation Effects 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 4
- ZBVSXOGAFJHROQ-UHFFFAOYSA-N 3-oxo-2-piperidin-4-yl-1h-isoindole-4-carboxamide;hydrochloride Chemical compound Cl.O=C1C=2C(C(=O)N)=CC=CC=2CN1C1CCNCC1 ZBVSXOGAFJHROQ-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 4
- KMLQJNMOKBITMT-UHFFFAOYSA-N Cl.OC(=O)c1cccc2CN(C3CCNCC3)C(=O)c12 Chemical compound Cl.OC(=O)c1cccc2CN(C3CCNCC3)C(=O)c12 KMLQJNMOKBITMT-UHFFFAOYSA-N 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- 230000005778 DNA damage Effects 0.000 description 4
- 231100000277 DNA damage Toxicity 0.000 description 4
- 230000033616 DNA repair Effects 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 4
- 230000007812 deficiency Effects 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 4
- 239000012894 fetal calf serum Substances 0.000 description 4
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 4
- 230000010287 polarization Effects 0.000 description 4
- 239000011591 potassium Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 4
- 235000010288 sodium nitrite Nutrition 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 229960004793 sucrose Drugs 0.000 description 4
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- VUAXHMVRKOTJKP-UHFFFAOYSA-M 2,2-dimethylbutanoate Chemical compound CCC(C)(C)C([O-])=O VUAXHMVRKOTJKP-UHFFFAOYSA-M 0.000 description 3
- XPERIYDUXDEQLZ-UHFFFAOYSA-N 4-fluoro-2-iodo-6-methylbenzoic acid Chemical compound CC1=CC(F)=CC(I)=C1C(O)=O XPERIYDUXDEQLZ-UHFFFAOYSA-N 0.000 description 3
- VWEBHAQVIIYCLE-UHFFFAOYSA-N 6-fluoro-2-(3-morpholin-4-ylpropyl)-3-oxo-1H-isoindole-4-carbonitrile Chemical compound Fc1cc2CN(CCCN3CCOCC3)C(=O)c2c(c1)C#N VWEBHAQVIIYCLE-UHFFFAOYSA-N 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 239000004342 Benzoyl peroxide Substances 0.000 description 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 229960003328 benzoyl peroxide Drugs 0.000 description 3
- 235000019400 benzoyl peroxide Nutrition 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 235000013681 dietary sucrose Nutrition 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 230000034431 double-strand break repair via homologous recombination Effects 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 230000006801 homologous recombination Effects 0.000 description 3
- 238000002744 homologous recombination Methods 0.000 description 3
- 231100000518 lethal Toxicity 0.000 description 3
- 230000001665 lethal effect Effects 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 229920000609 methyl cellulose Polymers 0.000 description 3
- 239000001923 methylcellulose Substances 0.000 description 3
- 235000010981 methylcellulose Nutrition 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 150000002940 palladium Chemical class 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 235000011118 potassium hydroxide Nutrition 0.000 description 3
- 238000005932 reductive alkylation reaction Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 230000005783 single-strand break Effects 0.000 description 3
- 229940001593 sodium carbonate Drugs 0.000 description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 239000013585 weight reducing agent Substances 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 2
- VTWSBILIFIFEFG-UHFFFAOYSA-N 2-bromo-4-fluoro-6-methylaniline Chemical compound CC1=CC(F)=CC(Br)=C1N VTWSBILIFIFEFG-UHFFFAOYSA-N 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- AOZCRPBUUBEYOW-UHFFFAOYSA-N 3-oxo-2-[1-(pyridin-4-ylmethyl)piperidin-4-yl]-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC=CC=2CN1C(CC1)CCN1CC1=CC=NC=C1 AOZCRPBUUBEYOW-UHFFFAOYSA-N 0.000 description 2
- NNGJMRZTTDHKBN-UHFFFAOYSA-N 4-(4-carbamoyl-3-oxo-1H-isoindol-2-yl)piperidine-1-carboxylic acid Chemical compound C(N)(=O)C=1C=CC=C2CN(C(C12)=O)C1CCN(CC1)C(=O)O NNGJMRZTTDHKBN-UHFFFAOYSA-N 0.000 description 2
- CJGTVMYPCZCUPH-UHFFFAOYSA-N 4-(furan-2-ylmethylamino)piperidine-1-carboxylic acid Chemical compound O1C(=CC=C1)CNC1CCN(CC1)C(=O)O CJGTVMYPCZCUPH-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- 0 BN(*)CC(Nc(cc1)cc(-c2ccccc22)c1NC2=O)=O Chemical compound BN(*)CC(Nc(cc1)cc(-c2ccccc22)c1NC2=O)=O 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- 239000012623 DNA damaging agent Substances 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 102000018825 Fanconi Anemia Complementation Group C protein Human genes 0.000 description 2
- 108010027673 Fanconi Anemia Complementation Group C protein Proteins 0.000 description 2
- 108010022012 Fanconi Anemia Complementation Group F protein Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 108010033040 Histones Proteins 0.000 description 2
- 102000006947 Histones Human genes 0.000 description 2
- 101000735456 Homo sapiens Protein mono-ADP-ribosyltransferase PARP3 Proteins 0.000 description 2
- 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 108091026813 Poly(ADPribose) Proteins 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000006011 Stroke Diseases 0.000 description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000004037 angiogenesis inhibitor Substances 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 230000033590 base-excision repair Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N beta-hydroxyethanesulfonic acid Natural products OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 230000004706 cardiovascular dysfunction Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 206010009887 colitis Diseases 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 230000003292 diminished effect Effects 0.000 description 2
- 230000005782 double-strand break Effects 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 210000004602 germ cell Anatomy 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical class C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 231100000225 lethality Toxicity 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- OEAASKJQPCOIPV-UHFFFAOYSA-N methyl 4-fluoro-2-iodo-6-methylbenzoate Chemical compound COC(=O)C1=C(C)C=C(F)C=C1I OEAASKJQPCOIPV-UHFFFAOYSA-N 0.000 description 2
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- RZFVLEJOHSLEFR-UHFFFAOYSA-N phenanthridone Chemical compound C1=CC=C2C(O)=NC3=CC=CC=C3C2=C1 RZFVLEJOHSLEFR-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 230000000770 proinflammatory effect Effects 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008223 sterile water Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 229910052721 tungsten Inorganic materials 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- 229940102001 zinc bromide Drugs 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- HFVMEOPYDLEHBR-UHFFFAOYSA-N (2-fluorophenyl)-phenylmethanol Chemical compound C=1C=CC=C(F)C=1C(O)C1=CC=CC=C1 HFVMEOPYDLEHBR-UHFFFAOYSA-N 0.000 description 1
- FZENGILVLUJGJX-NSCUHMNNSA-N (E)-acetaldehyde oxime Chemical compound C\C=N\O FZENGILVLUJGJX-NSCUHMNNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- JPRPJUMQRZTTED-UHFFFAOYSA-N 1,3-dioxolanyl Chemical group [CH]1OCCO1 JPRPJUMQRZTTED-UHFFFAOYSA-N 0.000 description 1
- VVKMHTWFAUCCOD-UHFFFAOYSA-N 1-(3-aminopropyl)-8-[3-[2-(dimethylamino)-2-oxoethyl]anilino]-n-[(2-methylpyridin-4-yl)methyl]-4,5-dihydropyrazolo[4,3-h]quinazoline-3-carboxamide Chemical group CN(C)C(=O)CC1=CC=CC(NC=2N=C3C=4N(CCCN)N=C(C=4CCC3=CN=2)C(=O)NCC=2C=C(C)N=CC=2)=C1 VVKMHTWFAUCCOD-UHFFFAOYSA-N 0.000 description 1
- LUDPAPHRXZBKJI-UHFFFAOYSA-N 1-benzyl-n-(furan-2-ylmethyl)piperidin-4-amine Chemical compound C=1C=COC=1CNC(CC1)CCN1CC1=CC=CC=C1 LUDPAPHRXZBKJI-UHFFFAOYSA-N 0.000 description 1
- IQJMTEVOTUFEIZ-UHFFFAOYSA-N 1-cyclohexyl-N-(furan-2-ylmethyl)piperidin-4-amine Chemical compound C1(CCCCC1)N1CCC(CC1)NCC=1OC=CC1 IQJMTEVOTUFEIZ-UHFFFAOYSA-N 0.000 description 1
- GZWFMQMAEUUNCC-UHFFFAOYSA-N 1-cyclohexylpiperidin-4-amine Chemical compound C1CC(N)CCN1C1CCCCC1 GZWFMQMAEUUNCC-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- KZLHJDVOUQSXAH-UHFFFAOYSA-N 2-(1-benzylpiperidin-4-yl)-3-oxo-1h-isoindole-4-carboxylic acid Chemical compound O=C1C=2C(C(=O)O)=CC=CC=2CN1C(CC1)CCN1CC1=CC=CC=C1 KZLHJDVOUQSXAH-UHFFFAOYSA-N 0.000 description 1
- ZOHDROVGNHNHKU-UHFFFAOYSA-N 2-(3,4-dihydro-1h-isoquinolin-2-yl)-n-(furan-2-ylmethyl)ethanamine Chemical compound C1CC2=CC=CC=C2CN1CCNCC1=CC=CO1 ZOHDROVGNHNHKU-UHFFFAOYSA-N 0.000 description 1
- PLEHXIXSSZMKLS-UHFFFAOYSA-N 2-(3,4-dihydro-2h-quinolin-1-yl)-n-(furan-2-ylmethyl)ethanamine Chemical compound C1CCC2=CC=CC=C2N1CCNCC1=CC=CO1 PLEHXIXSSZMKLS-UHFFFAOYSA-N 0.000 description 1
- YYBMXUWJUDNBBU-UHFFFAOYSA-N 2-[1-(4,4-dimethylcyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-1h-isoindole-4-carboxamide Chemical compound C1CC(C)(C)CCC1N1CCC(N2C(C3=C(C(N)=O)C=C(F)C=C3C2)=O)CC1 YYBMXUWJUDNBBU-UHFFFAOYSA-N 0.000 description 1
- FFIYKQCBUSMRHR-UHFFFAOYSA-N 2-benzyl-3-oxo-1h-isoindole-4-carboxylic acid Chemical compound O=C1C=2C(C(=O)O)=CC=CC=2CN1CC1=CC=CC=C1 FFIYKQCBUSMRHR-UHFFFAOYSA-N 0.000 description 1
- IXUWQVSJMYQPNQ-UHFFFAOYSA-N 2-piperidin-4-yl-1,3-dihydroisoindole-4-carboxamide;hydrochloride Chemical compound Cl.C1C=2C(C(=O)N)=CC=CC=2CN1C1CCNCC1 IXUWQVSJMYQPNQ-UHFFFAOYSA-N 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- UIKUBYKUYUSRSM-UHFFFAOYSA-N 3-morpholinopropylamine Chemical compound NCCCN1CCOCC1 UIKUBYKUYUSRSM-UHFFFAOYSA-N 0.000 description 1
- LTNBJPASIMOEQG-UHFFFAOYSA-N 3-oxo-1,2-dihydroisoindole-4-carboxamide Chemical class NC(=O)C1=CC=CC2=C1C(=O)NC2 LTNBJPASIMOEQG-UHFFFAOYSA-N 0.000 description 1
- QXPFWOWMEUOMBP-UHFFFAOYSA-N 3-oxo-1-(2-phenylethyl)-1,2-dihydroisoindole-4-carboxylic acid Chemical compound O=C1NC(C=2C=CC=C(C1=2)C(=O)O)CCC1=CC=CC=C1 QXPFWOWMEUOMBP-UHFFFAOYSA-N 0.000 description 1
- QNYZTKWMJGMZQX-UHFFFAOYSA-N 3-oxo-2-piperidin-4-yl-1h-isoindole-4-carboxylic acid Chemical compound O=C1C=2C(C(=O)O)=CC=CC=2CN1C1CCNCC1 QNYZTKWMJGMZQX-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 1
- HJANUOODDUTANI-UHFFFAOYSA-N 4-[9-(dimethylamino)-11,11-dimethyl-3,4-dihydro-2h-naphtho[2,3-g]quinolin-1-ium-1-yl]-n-[3-[[2-oxo-2-[(6-oxo-5h-phenanthridin-2-yl)amino]ethyl]amino]propyl]butanamide;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.C1=CC=C2C3=CC(NC(=O)CNCCCNC(=O)CCC[N+]=4CCCC5=CC6=CC7=CC=C(C=C7C(C)(C)C6=CC5=4)N(C)C)=CC=C3NC(=O)C2=C1 HJANUOODDUTANI-UHFFFAOYSA-N 0.000 description 1
- OHGZMKRXWXMIIH-UHFFFAOYSA-N 4-[9-(dimethylamino)-11,11-dimethyl-3,4-dihydro-2h-naphtho[2,3-g]quinolin-1-ium-1-yl]-n-[6-[[2-oxo-2-[(6-oxo-5h-phenanthridin-2-yl)amino]ethyl]amino]hexyl]butanamide;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.C1=CC=C2C3=CC(NC(=O)CNCCCCCCNC(=O)CCC[N+]=4CCCC5=CC6=CC7=CC=C(C=C7C(C)(C)C6=CC5=4)N(C)C)=CC=C3NC(=O)C2=C1 OHGZMKRXWXMIIH-UHFFFAOYSA-N 0.000 description 1
- AFEIOLJUSBYFIZ-UHFFFAOYSA-N 4-[9-(dimethylamino)-11,11-dimethyl-3,4-dihydro-2h-naphtho[2,3-g]quinolin-1-ium-1-yl]-n-methyl-n-[2-oxo-2-[(6-oxo-5h-phenanthridin-2-yl)amino]ethyl]butanamide;2,2,2-trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F.C1=CC=C2C3=CC(NC(=O)CN(C)C(=O)CCC[N+]=4CCCC5=CC6=CC7=CC=C(C=C7C(C)(C)C6=CC5=4)N(C)C)=CC=C3NC(=O)C2=C1 AFEIOLJUSBYFIZ-UHFFFAOYSA-N 0.000 description 1
- NQNQKLBWDARKDG-UHFFFAOYSA-N 4-amino-1-piperidinecarboxylic acid Chemical compound NC1CCN(C(O)=O)CC1 NQNQKLBWDARKDG-UHFFFAOYSA-N 0.000 description 1
- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- NRGODQXXFRRYEH-UHFFFAOYSA-N 6-fluoro-3-oxo-2-(1-spiro[2.5]octan-6-ylpiperidin-4-yl)-1h-isoindole-4-carboxamide Chemical compound O=C1C=2C(C(=O)N)=CC(F)=CC=2CN1C(CC1)CCN1C(CC1)CCC21CC2 NRGODQXXFRRYEH-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- SRNWOUGRCWSEMX-TYASJMOZSA-N ADP-D-ribose Chemical compound C([C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=2N=CN=C(C=2N=C1)N)OP(O)(=O)OP(O)(=O)OC[C@H]1OC(O)[C@H](O)[C@@H]1O SRNWOUGRCWSEMX-TYASJMOZSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 102000036365 BRCA1 Human genes 0.000 description 1
- 108700020463 BRCA1 Proteins 0.000 description 1
- 102000052609 BRCA2 Human genes 0.000 description 1
- 108700020462 BRCA2 Proteins 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical class OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- UUNRBEUBXCOJRJ-UHFFFAOYSA-N C(C1=CC=CC=C1)C1CCN(CC1)CCCNCC=1OC=CC1 Chemical compound C(C1=CC=CC=C1)C1CCN(CC1)CCCNCC=1OC=CC1 UUNRBEUBXCOJRJ-UHFFFAOYSA-N 0.000 description 1
- XNBOZNXCZZOTHN-UHFFFAOYSA-N C(C1=CC=CC=C1)N1CCC(CC1)CCNCC=1OC=CC1 Chemical compound C(C1=CC=CC=C1)N1CCC(CC1)CCNCC=1OC=CC1 XNBOZNXCZZOTHN-UHFFFAOYSA-N 0.000 description 1
- LPTJRPGJRALCOU-UHFFFAOYSA-O CC(C)(c1cc(N(C)C)ccc1C=C1C=C2CCC[NH2+]CCCN=O)C1=CC2=C Chemical compound CC(C)(c1cc(N(C)C)ccc1C=C1C=C2CCC[NH2+]CCCN=O)C1=CC2=C LPTJRPGJRALCOU-UHFFFAOYSA-O 0.000 description 1
- CBPSXDSMHNPFNI-UHFFFAOYSA-N CC1CCCC(C)N1CCCN1Cc2cccc(C(O)=O)c2C1=O Chemical compound CC1CCCC(C)N1CCCN1Cc2cccc(C(O)=O)c2C1=O CBPSXDSMHNPFNI-UHFFFAOYSA-N 0.000 description 1
- QTASUEORYJCBBN-UHFFFAOYSA-N CN1CCN(CCCN2Cc3cccc(C(O)=O)c3C2=O)CC1 Chemical compound CN1CCN(CCCN2Cc3cccc(C(O)=O)c3C2=O)CC1 QTASUEORYJCBBN-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 229940123587 Cell cycle inhibitor Drugs 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- TZBOFHCYWSRRNX-UHFFFAOYSA-N Cl.CC1CCCC(C)N1CCCN1Cc2cccc(C(N)=O)c2C1=O Chemical compound Cl.CC1CCCC(C)N1CCCN1Cc2cccc(C(N)=O)c2C1=O TZBOFHCYWSRRNX-UHFFFAOYSA-N 0.000 description 1
- NNOQRYFPQQXMDE-UHFFFAOYSA-N Cl.Cl.N1(CCCCC1)C1CCN(CC1)CCCN1CC=2C=CC=C(C2C1=O)C(=O)N Chemical compound Cl.Cl.N1(CCCCC1)C1CCN(CC1)CCCN1CC=2C=CC=C(C2C1=O)C(=O)N NNOQRYFPQQXMDE-UHFFFAOYSA-N 0.000 description 1
- PFROUMIGDXOKKO-UHFFFAOYSA-N Cl.NC(=O)c1cccc2CN(CCC3CCN(Cc4ccccc4)CC3)C(=O)c12 Chemical compound Cl.NC(=O)c1cccc2CN(CCC3CCN(Cc4ccccc4)CC3)C(=O)c12 PFROUMIGDXOKKO-UHFFFAOYSA-N 0.000 description 1
- VVGALVLHLOFACV-UHFFFAOYSA-N Cl.NC(=O)c1cccc2CN(CCCN3CCCCC3)C(=O)c12 Chemical compound Cl.NC(=O)c1cccc2CN(CCCN3CCCCC3)C(=O)c12 VVGALVLHLOFACV-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 102000011724 DNA Repair Enzymes Human genes 0.000 description 1
- 108010076525 DNA Repair Enzymes Proteins 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 101150029113 EMSY gene Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 102000009095 Fanconi Anemia Complementation Group A protein Human genes 0.000 description 1
- 108010087740 Fanconi Anemia Complementation Group A protein Proteins 0.000 description 1
- 102000013601 Fanconi Anemia Complementation Group D2 protein Human genes 0.000 description 1
- 108010026653 Fanconi Anemia Complementation Group D2 protein Proteins 0.000 description 1
- 102000012216 Fanconi Anemia Complementation Group F protein Human genes 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000684297 Homo sapiens 26S proteasome complex subunit SEM1 Proteins 0.000 description 1
- 101000729474 Homo sapiens DNA-directed RNA polymerase I subunit RPA1 Proteins 0.000 description 1
- 101001128138 Homo sapiens NACHT, LRR and PYD domains-containing protein 2 Proteins 0.000 description 1
- 101000981336 Homo sapiens Nibrin Proteins 0.000 description 1
- 101000873438 Homo sapiens Putative protein SEM1, isoform 2 Proteins 0.000 description 1
- 101001092125 Homo sapiens Replication protein A 70 kDa DNA-binding subunit Proteins 0.000 description 1
- 101000835998 Homo sapiens SRA stem-loop-interacting RNA-binding protein, mitochondrial Proteins 0.000 description 1
- 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 description 1
- 101000904868 Homo sapiens Transcriptional regulator ATRX Proteins 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 102000016878 Hypoxia-Inducible Factor 1 Human genes 0.000 description 1
- 108010028501 Hypoxia-Inducible Factor 1 Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 1
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 208000007201 Myocardial reperfusion injury Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- WKJHLUGTMVZSGR-UHFFFAOYSA-N N-(furan-2-ylmethyl)-3-(4-phenylpiperazin-1-yl)propan-1-amine Chemical compound O1C(=CC=C1)CNCCCN1CCN(CC1)C1=CC=CC=C1 WKJHLUGTMVZSGR-UHFFFAOYSA-N 0.000 description 1
- WLRRVCDZJUXSKX-UHFFFAOYSA-N N-(furan-2-ylmethyl)-3-(4-piperidin-1-ylpiperidin-1-yl)propan-1-amine Chemical compound N1(CCCCC1)C1CCN(CC1)CCCNCC=1OC=CC1 WLRRVCDZJUXSKX-UHFFFAOYSA-N 0.000 description 1
- ZCLKVMQSJPNQOW-UHFFFAOYSA-N N1(CCCC2=CC=CC=C12)CCCNCC=1OC=CC1 Chemical compound N1(CCCC2=CC=CC=C12)CCCNCC=1OC=CC1 ZCLKVMQSJPNQOW-UHFFFAOYSA-N 0.000 description 1
- DRWJYMDBILDQHF-UHFFFAOYSA-N N1(CCCCC1)C1CCN(CC1)CCCN1CC=2C=CC=C(C2C1=O)C(=O)O Chemical compound N1(CCCCC1)C1CCN(CC1)CCCN1CC=2C=CC=C(C2C1=O)C(=O)O DRWJYMDBILDQHF-UHFFFAOYSA-N 0.000 description 1
- QMFJNBILTNXCGW-UHFFFAOYSA-N NC(c(cccc1CN2CCc3ccccc3)c1C2=O)=O Chemical compound NC(c(cccc1CN2CCc3ccccc3)c1C2=O)=O QMFJNBILTNXCGW-UHFFFAOYSA-N 0.000 description 1
- 101100221809 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cpd-7 gene Proteins 0.000 description 1
- 102100024403 Nibrin Human genes 0.000 description 1
- 102000007999 Nuclear Proteins Human genes 0.000 description 1
- 108010089610 Nuclear Proteins Proteins 0.000 description 1
- XECKYPDTPYYYIO-UHFFFAOYSA-N O=C1N=[O]=C2N(CCCN(CC3)CCN3c3ccccc3)Cc3c2c1ccc3 Chemical compound O=C1N=[O]=C2N(CCCN(CC3)CCN3c3ccccc3)Cc3c2c1ccc3 XECKYPDTPYYYIO-UHFFFAOYSA-N 0.000 description 1
- LZBUNACAWVSGNC-UHFFFAOYSA-N O=C1N=[O]=C2N(CCCN(CC3)Cc4c3cccc4)Cc3c2c1ccc3 Chemical compound O=C1N=[O]=C2N(CCCN(CC3)Cc4c3cccc4)Cc3c2c1ccc3 LZBUNACAWVSGNC-UHFFFAOYSA-N 0.000 description 1
- ROZQEQPKOSQSHO-UHFFFAOYSA-N OC(=O)c1cccc2CN(C3CCN(CC3)C3CCCCC3)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(C3CCN(CC3)C3CCCCC3)C(=O)c12 ROZQEQPKOSQSHO-UHFFFAOYSA-N 0.000 description 1
- GGMHZFHDALMWFF-UHFFFAOYSA-N OC(=O)c1cccc2CN(C3CCN(CC3)C3CCOCC3)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(C3CCN(CC3)C3CCOCC3)C(=O)c12 GGMHZFHDALMWFF-UHFFFAOYSA-N 0.000 description 1
- DFPBYBYXBYZVJO-UHFFFAOYSA-N OC(=O)c1cccc2CN(CCC3CCN(Cc4ccccc4)CC3)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(CCC3CCN(Cc4ccccc4)CC3)C(=O)c12 DFPBYBYXBYZVJO-UHFFFAOYSA-N 0.000 description 1
- XAJZKGBAKBPUSS-UHFFFAOYSA-N OC(=O)c1cccc2CN(CCCN3CCC(Cc4ccccc4)CC3)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(CCCN3CCC(Cc4ccccc4)CC3)C(=O)c12 XAJZKGBAKBPUSS-UHFFFAOYSA-N 0.000 description 1
- SCTLEKZERSIHAX-UHFFFAOYSA-N OC(=O)c1cccc2CN(CCCN3CCCCC3)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(CCCN3CCCCC3)C(=O)c12 SCTLEKZERSIHAX-UHFFFAOYSA-N 0.000 description 1
- YIDCPPNGXRCPBT-UHFFFAOYSA-N OC(=O)c1cccc2CN(CCCN3CCCc4ccccc34)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(CCCN3CCCc4ccccc34)C(=O)c12 YIDCPPNGXRCPBT-UHFFFAOYSA-N 0.000 description 1
- OUYFTWAEWUJLRH-UHFFFAOYSA-N OC(=O)c1cccc2CN(CCCN3CCN(CC3)c3ccccc3)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(CCCN3CCN(CC3)c3ccccc3)C(=O)c12 OUYFTWAEWUJLRH-UHFFFAOYSA-N 0.000 description 1
- BYCKTEPDKKQPRY-UHFFFAOYSA-N OC(=O)c1cccc2CN(CCCN3CCOCC3)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(CCCN3CCOCC3)C(=O)c12 BYCKTEPDKKQPRY-UHFFFAOYSA-N 0.000 description 1
- FZULOGXVLLJPQV-UHFFFAOYSA-N OC(=O)c1cccc2CN(CCCN3CCc4ccccc4C3)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(CCCN3CCc4ccccc4C3)C(=O)c12 FZULOGXVLLJPQV-UHFFFAOYSA-N 0.000 description 1
- JDUGUPBLSCIUGK-UHFFFAOYSA-N OC(=O)c1cccc2CN(CCCc3ccccc3)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(CCCc3ccccc3)C(=O)c12 JDUGUPBLSCIUGK-UHFFFAOYSA-N 0.000 description 1
- NVWWOVRMKQVQGD-UHFFFAOYSA-N OC(=O)c1cccc2CN(CCN3CCCCC3)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(CCN3CCCCC3)C(=O)c12 NVWWOVRMKQVQGD-UHFFFAOYSA-N 0.000 description 1
- ZHHNLDDCQZZBOZ-UHFFFAOYSA-N OC(=O)c1cccc2CN(CCN3CCCc4ccccc34)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(CCN3CCCc4ccccc34)C(=O)c12 ZHHNLDDCQZZBOZ-UHFFFAOYSA-N 0.000 description 1
- BSCPLIYDBPYWJQ-UHFFFAOYSA-N OC(=O)c1cccc2CN(CCN3CCOCC3)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(CCN3CCOCC3)C(=O)c12 BSCPLIYDBPYWJQ-UHFFFAOYSA-N 0.000 description 1
- SMSWITCLFSDZCP-UHFFFAOYSA-N OC(=O)c1cccc2CN(CCc3ccccn3)C(=O)c12 Chemical compound OC(=O)c1cccc2CN(CCc3ccccn3)C(=O)c12 SMSWITCLFSDZCP-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 229940127397 Poly(ADP-Ribose) Polymerase Inhibitors Drugs 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 208000033759 Prolymphocytic T-Cell Leukemia Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102100034920 Putative protein SEM1, isoform 2 Human genes 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 102000002490 Rad51 Recombinase Human genes 0.000 description 1
- 108010068097 Rad51 Recombinase Proteins 0.000 description 1
- 102100035729 Replication protein A 70 kDa DNA-binding subunit Human genes 0.000 description 1
- 102100025491 SRA stem-loop-interacting RNA-binding protein, mitochondrial Human genes 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- XYQRXRFVKUPBQN-UHFFFAOYSA-L Sodium carbonate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]C([O-])=O XYQRXRFVKUPBQN-UHFFFAOYSA-L 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000026651 T-cell prolymphocytic leukemia Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 1
- 102100023931 Transcriptional regulator ATRX Human genes 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 206010046851 Uveitis Diseases 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- ZBIKORITPGTTGI-UHFFFAOYSA-N [acetyloxy(phenyl)-$l^{3}-iodanyl] acetate Chemical compound CC(=O)OI(OC(C)=O)C1=CC=CC=C1 ZBIKORITPGTTGI-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- RQBBFKINEJYDOB-UHFFFAOYSA-N acetic acid;acetonitrile Chemical compound CC#N.CC(O)=O RQBBFKINEJYDOB-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 230000002942 anti-growth Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- VKVGTVNGANWQHP-UHFFFAOYSA-N azane 2H-benzotriazol-4-ol Chemical compound N.OC1=CC=CC2=C1N=NN2 VKVGTVNGANWQHP-UHFFFAOYSA-N 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 235000011116 calcium hydroxide Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000001351 cycling effect Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical class CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000012361 double-strand break repair Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000007888 film coating Substances 0.000 description 1
- 238000009501 film coating Methods 0.000 description 1
- 238000002875 fluorescence polarization Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 201000011045 hereditary breast ovarian cancer syndrome Diseases 0.000 description 1
- 229940125697 hormonal agent Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002431 hydrogen Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 239000000677 immunologic agent Substances 0.000 description 1
- 229940124541 immunological agent Drugs 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 150000002471 indium Chemical class 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229940030980 inova Drugs 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- XTBAPWCYTNCZTO-UHFFFAOYSA-N isoindol-1-one Chemical class C1=CC=C2C(=O)N=CC2=C1 XTBAPWCYTNCZTO-UHFFFAOYSA-N 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 229960004393 lidocaine hydrochloride Drugs 0.000 description 1
- YECIFGHRMFEPJK-UHFFFAOYSA-N lidocaine hydrochloride monohydrate Chemical compound O.[Cl-].CC[NH+](CC)CC(=O)NC1=C(C)C=CC=C1C YECIFGHRMFEPJK-UHFFFAOYSA-N 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical class [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 235000012254 magnesium hydroxide Nutrition 0.000 description 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 229940126619 mouse monoclonal antibody Drugs 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- LQZPJQKYAOYUJS-UHFFFAOYSA-N n,n-diethyl-2-phenothiazin-10-ylethanamine;hydron;chloride Chemical compound Cl.C1=CC=C2N(CCN(CC)CC)C3=CC=CC=C3SC2=C1 LQZPJQKYAOYUJS-UHFFFAOYSA-N 0.000 description 1
- WDTGNYDDCJERKR-UHFFFAOYSA-N n-(furan-2-ylmethyl)-1-phenylmethanamine Chemical compound C=1C=COC=1CNCC1=CC=CC=C1 WDTGNYDDCJERKR-UHFFFAOYSA-N 0.000 description 1
- XODQIXKMHPJBFF-UHFFFAOYSA-N n-(furan-2-ylmethyl)-2-morpholin-4-ylethanamine Chemical compound C=1C=COC=1CNCCN1CCOCC1 XODQIXKMHPJBFF-UHFFFAOYSA-N 0.000 description 1
- PAZJDKKSVLFGPT-UHFFFAOYSA-N n-(furan-2-ylmethyl)-2-phenylethanamine Chemical compound C=1C=COC=1CNCCC1=CC=CC=C1 PAZJDKKSVLFGPT-UHFFFAOYSA-N 0.000 description 1
- LXYJWYBKBPPUGF-UHFFFAOYSA-N n-(furan-2-ylmethyl)-2-piperidin-1-ylethanamine Chemical compound C=1C=COC=1CNCCN1CCCCC1 LXYJWYBKBPPUGF-UHFFFAOYSA-N 0.000 description 1
- KUQJAVXUDNIBTC-UHFFFAOYSA-N n-(furan-2-ylmethyl)-3-(4-methylpiperazin-1-yl)propan-1-amine Chemical compound C1CN(C)CCN1CCCNCC1=CC=CO1 KUQJAVXUDNIBTC-UHFFFAOYSA-N 0.000 description 1
- ILBCZZMPZQMCOJ-UHFFFAOYSA-N n-(furan-2-ylmethyl)-3-morpholin-4-ylpropan-1-amine Chemical compound C1COCCN1CCCNCC1=CC=CO1 ILBCZZMPZQMCOJ-UHFFFAOYSA-N 0.000 description 1
- BDGLUZWDLUQQBU-UHFFFAOYSA-N n-(furan-2-ylmethyl)-3-phenylpropan-1-amine Chemical compound C=1C=CC=CC=1CCCNCC1=CC=CO1 BDGLUZWDLUQQBU-UHFFFAOYSA-N 0.000 description 1
- KHZUXLWLVRLXSX-UHFFFAOYSA-N n-(furan-2-ylmethyl)-3-piperidin-1-ylpropan-1-amine Chemical compound C1CCCCN1CCCNCC1=CC=CO1 KHZUXLWLVRLXSX-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229920001206 natural gum Polymers 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 235000005152 nicotinamide Nutrition 0.000 description 1
- 239000011570 nicotinamide Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 229940078552 o-xylene Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 1
- 229960000572 olaparib Drugs 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000009521 phase II clinical trial Methods 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-O phosphonium Chemical compound [PH4+] XYFCBTPGUUZFHI-UHFFFAOYSA-O 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- HMABYWSNWIZPAG-UHFFFAOYSA-N rucaparib Chemical compound C1=CC(CNC)=CC=C1C(N1)=C2CCNC(=O)C3=C2C1=CC(F)=C3 HMABYWSNWIZPAG-UHFFFAOYSA-N 0.000 description 1
- 229950004707 rucaparib Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229940018038 sodium carbonate decahydrate Drugs 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- 229960001922 sodium perborate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- YKLJGMBLPUQQOI-UHFFFAOYSA-M sodium;oxidooxy(oxo)borane Chemical compound [Na+].[O-]OB=O YKLJGMBLPUQQOI-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 229910052717 sulfur Chemical group 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000003277 telomerase inhibitor Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 230000000472 traumatic effect Effects 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- JNAHVYVRKWKWKQ-CYBMUJFWSA-N veliparib Chemical compound N=1C2=CC=CC(C(N)=O)=C2NC=1[C@@]1(C)CCCN1 JNAHVYVRKWKWKQ-CYBMUJFWSA-N 0.000 description 1
- 229950011257 veliparib Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/4035—Isoindoles, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the present invention provides novel substituted 4-carboxamido-isoindolinone derivatives which proved to be potent and selective poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors with respect to poly (ADP-ribose) polymerase-2 (PARP-2) and are thus useful in the therapy of cancer, cardiovascular diseases, nervous system injury and inflammation.
- PARP-1 ADP-ribose polymerase-1
- PARP-2 poly (ADP-ribose) polymerase-2
- the present invention also provides methods for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.
- Poly (ADP-ribose) polymerases belong to a family of 18 members that catalyze the addition of ADP-ribose units to DNA or different acceptor proteins, which affect cellular processes as diverse as replication, transcription, differentiation, gene regulation, protein degradation and spindle maintenance.
- PARP-1 and PARP-2 are the only enzymes among the PARPs that are activated by DNA damage and are involved in DNA repair.
- PARP-1 is a nuclear protein consisting of three domains: the N-terminal DNA-binding domain containing two zinc fingers, the auto modification domain, and the C-terminal catalytic domain. PARP-1 binds through the zinc-finger domain to DNA single strand breaks (SSB), cleaves NAD + , and attaches multiple ADP-ribose units to target proteins such as histones and various DNA repair enzymes. This results in a highly negatively charged target, which in turn leads to the unwinding and repair of the damaged DNA through the base excision repair pathway. In knock out mouse models, deletion of PARP-1 impairs DNA repair but it is not embryonic lethal.
- SSB DNA single strand breaks
- Enhanced PARP-1 expression and/or activity have been shown in different tumor cell lines, including malignant lymphomas, hepatocellular carcinoma, cervical carcinoma, colorectal carcinoma, leukemia. This may allow tumor cells to withstand genotoxic stress and increase their resistance to DNA-damaging agents.
- inhibition of PARP-1 through small molecules has been shown to sensitize tumor cells to cytotoxic therapy (e.g. temozolomide, platinums, topoisomerase inhibitors and radiation).
- cytotoxic therapy e.g. temozolomide, platinums, topoisomerase inhibitors and radiation.
- PARP inhibitors may be more effective in patients with tumors with specific DNA repair defects without affecting normal heterozygous tissues.
- Putative patient population includes, besides BRCA mutants that represent the majority of hereditary breast and ovarian cancer, also a substantial fraction of sporadic cancers with defects in homologous recombination repair, a phenomenon termed "BRCAness". For example, methylation of the promoters of the BRCA-1 or FANCF genes and amplification of the EMSY gene, which encodes a BRCA-2 interacting protein.
- PARP-1 has also been implicated in angiogenesis.
- PARP-1 inhibition seems to result in decreased accumulation of the transcription hypoxia-inducible factor 1 a, an important regulator of tumor cell adaptation to hypoxia.
- Pro-inflammatory stimuli trigger the release of pro-inflammatory mediators that induce the production of peroxynitrate and hydroxyl radicals, which in turn yield to DNA single strand breakage with consequent activation of PARP-1.
- Over activation of PARP-1 results in depletion of NAD+ and energy stores, culminating in cell dysfunction and necrosis.
- This cellular suicide mechanism has been implicated in the pathomechanism of stroke, myocardial ischemia, diabetes, diabetes-associated cardiovascular dysfunction, shock, traumatic central nervous system injury, arthritis, colitis, allergic encephalomyelitis and various other forms of inflammation.
- PARP-1 nuclear factor kB-mediated transcription, which plays a central role in the expression of inflammatory cytokines, chemokines and inflammatory mediators.
- WO 2007/047646 in the name of Janssen Pharmaceutica describes substituted dihydro-isoindolones useful for treating kinase disorders; Wender et al. claim in US 7,232,842 isoindolone analogs as kinase inhibitors.
- the Patent Application US 2008/0108659 of Khan et al. describes 3-oxo-2,3-dihydro-1 H-isoindoles as poly (ADP-ribose) polymerase inhibitors, also reported in: Bioorg. Med. Chem. Lett., 2010, 20, 1023-1026.
- WO 2011/006794 and WO 2011/006803 both in the name of Nerviano Medical Sciences, describe 3-oxo-2,3-dihydro-1 H-isoindole-4- carboxamides as selective PARP-1 inhibitors.
- the present invention provides novel substituted 4-carboxamido-isoindolinone derivatives which proved to be potent and selective PARP-1 inhibitors with respect to PARP-2 and are thus useful in the therapy of cancer, cardiovascular diseases, nervous system injury and inflammation.
- the present invention also provides method for preparing these compounds, pharmaceutical compositions comprising these compounds, and methods of treating diseases utilizing pharmaceutical compositions comprising these compounds.
- a first object of the present invention is to provide a compound of formula (I):
- R is hydrogen or fluorine
- n, m, R1 and R2 have the following meanings:
- n 0 and m is 0, 1 , 2 or 3;
- R1 is 3- to 6-membered cycloalkyi or 4- to 6-membered heterocyclyl
- R2 is a 3-, 5- or 6-membered cycloalkyi, 4- to 6-membered heterocyclyl, aryl or heteroaryl;
- n 1 and m is 0;
- R1 is 3- to 6-membered cycloalkyi or aryl, each of which optionally further substituted with one or more linear or branched (Ci-Ce)-alkyl;
- R2 is null, 3- to 6-membered cycloalkyi, 4- to 6-membered heterocyclyl, aryl or heteroaryl, each of which optionally further substituted with one or more linear or branched (Ci-Ce)-alkyl;
- n 2 or 3, and m is 0;
- R1 is a 3- to 6-membered cycloalkyi, 4- to 6-membered heterocyclyl, aryl or heteroaryl, each of which optionally further substituted with one or more linear or branched (Ci-Ce)-alkyl;
- R2 is null, 3- to 6-membered cycloalkyi, 4- to 6-membered heterocyclyl, aryl or heteroaryl, each of which optionally further substituted with one or more linear or branched (Ci-Ce)-alkyl;
- n and m are each independently 1 , 2 or 3;
- R1 and R2 are each independently 3- to 6-membered cycloalkyi, 4- to 6-membered heterocyclyl, aryl or heteroaryl; or a pharmaceutically acceptable salt thereof.
- the compounds of formula (I) as defined above are potent and selective PARP-1 inhibitors with respect to PARP-2 and are thus useful in cancer, cardiovascular diseases, nervous system injury and inflammation therapy.
- the present invention also provides methods of synthesizing substituted 4-carboxamido-isoindolinone derivatives of formula (I) as defined above, through a process consisting of standard synthetic transformations.
- the present invention also provides a method for treating diseases mediated by PARP-1 protein which comprises administering to a mammal in need thereof, preferably a human, an effective amount of a compound of formula (I), as defined above.
- a preferred method of the present invention is to treat a disease mediated by PARP-1 protein selected from the group consisting of cancer, cardiovascular diseases, nervous system injury and inflammation.
- carcinomas such as bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, esophagus, gall- bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma
- hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkitt's lymphoma
- hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias, myelodysplasia syndrome and promyelocytic leukemia
- tumors of mesenchymal origin including fibrosarcoma
- the method of the present invention also provides tumor angiogenesis and metastasis inhibition.
- Another preferred method of the present invention is to treat specific types of cardiovascular diseases including, but not limited to, myocardial reperfusion injury, cardiomyopathy, diabetic cardiovascular dysfunction.
- Another preferred method of the present invention is to treat specific types of nervous system injury including but not limited to: stroke, brain injury and neurodegenerative disorders.
- Another preferred method of the present invention is to treat specific types of inflammation diseases including, but not limited to, colitis, arthritis and uveitis.
- the present invention also provides an in vitro method for selectively inhibiting PARP-1 protein activity which comprises contacting the said protein with an effective amount of a compound of formula (I), as defined above.
- the present invention further provides a method for treating diseases comprising a compound of formula (I), as defined above, in combination with radiation therapy or chemotherapy regimen for simultaneous, separate or sequential use in anticancer therapy.
- the present invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, and at least one pharmaceutically acceptable excipient, carrier or diluent.
- the pharmaceutical composition of the present invention may further comprise one or more chemotherapeutic - e.g. cytostatic or cytotoxic - agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2 inhibitors), matrix metalloproteinases inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti-growth factor receptor agents, anti-HER agents, anti-EGFR agents, anti-angiogenesis agents (e.g.
- chemotherapeutic e.g. cytostatic or cytotoxic - agents, antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, cyclooxygenase inhibitors (e.g. COX-2 inhibitors), matrix metalloproteinases inhibitors, telomerase inhibitors, tyrosine kinase inhibitors, anti
- the chemotherapeutic agent is an alkylating agent. Even more preferably, the alkylating agent is temozolomide.
- the invention provides a product comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, and one or more chemotherapeutic agents, as a combined preparation for simultaneous, separate or sequential use in anticancer therapy.
- the chemotherapeutic agent is an alkylating agent.
- the alkylating agent is temozolomide.
- the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use as a medicament, preferably as a medicament with anticancer activity.
- the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, for use in a method of treating cancer.
- the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined above, in the manufacture of a medicament with anticancer activity.
- the compounds of formula (I) may have one or more asymmetric centers, and may therefore exist as individual optical isomers or racemic mixtures or diastereoisomers. Accordingly, all the possible isomers, and their mixtures of the compounds of formula (I) are within the scope of the present invention. As stated above, salts of the compounds of formula (I) are also within the scope of the present invention.
- the present invention includes all of the isomers, tautomers, hydrates, solvates, W-oxides and pharmaceutically acceptable salts of the compounds of this invention.
- each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
- halogen we intend a fluorine, chlorine, bromine or iodine atom.
- linear or branched (Ci-CeJ-alkyl) we intend any of the groups such as, for instance, methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, ferf-butyl, sec-butyl, n-pentyl, n-hexyl, and the like.
- 3- to 6-membered cycloalkyl we intend, unless otherwise provided, a 3- to 6-membered all-carbon monocyclic ring, which may contain one or more double bonds but does not have a completely conjugated ⁇ -electron system.
- cycloalkyl groups without limitation, are cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cyclohexadienyl.
- heterocyclyl a 4- to 6-membered, saturated or partially unsaturated carbocyclic ring where one or more carbon atoms are replaced by heteroatoms such as nitrogen, oxygen and sulfur; the heterocyclyl ring can be optionally further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings.
- heterocyclyl groups are, for instance, pyranyl, pyrrolidinyl, pyrrolinyl, imidazolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, thiazolinyl, thiazolidinyl, dihydrofuranyl, tetrahydrofuranyl, 1 ,3- dioxolanyl, piperidinyl, piperazinyl, morpholinyl and the like.
- aryl refers to a mono-, bi- or poly-carbocyclic hydrocarbon with from 1 to 4 ring systems, optionally further fused or linked to each other by single bonds, wherein at least one of the carbocyclic rings is "aromatic", wherein the term “aromatic” refers to completely conjugated ⁇ -electron bond system.
- aryl groups are phenyl, a- or ⁇ -naphthyl or biphenyl groups.
- heteroaryl refers to aromatic heterocyclic rings, typically 5- to 8-membered heterocycles with from 1 to 3 heteroatoms selected among N, 0 or S; the heteroaryl ring can be optionally further fused or linked to aromatic and non-aromatic carbocyclic and heterocyclic rings.
- heteroaryl groups are, for instance, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolyl, phenyl-pyrrolyl, furyl, phenyl-furyl, oxazolyl, isoxazolyl, pyrazolyl, thienyl, benzothienyl, isoindolinyl, benzoimidazolyl, indazolyl, quinolinyl, isoquinolinyl, 1 ,2,3-triazolyl, 1 -phenyl-1 ,2,3-triazolyl, 2,3-dihydroindolyl, 2,3-dihydrobenzofuranyl, 2,3- dihydrobenzothiophenyl; benzopyranyl, 2,3-dihydrobenzoxazinyl
- any of the above mentioned groups when any of the above mentioned groups is optionally substituted, it may be substituted in any of its free position by one or more linear or branched (0 ⁇ -0 ⁇ ) alkyl groups.
- pharmaceutically acceptable salt of compounds of formula (I) refers to those salts that retain the biological effectiveness and properties of the parent compound, therefore pharmaceutically acceptable salts of the compounds of formula (I) include the acid addition salts with inorganic or organic acids, e.g., nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, trifluoroacetic, propionic, glycolic, (D) or (L) lactic, oxalic, ascorbic, fumaric, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulphonic, ethanesulfonic, p- toluenesulfonic, isethionic, succinic and salicylic acid.
- inorganic or organic acids e.g., nitric, hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, acetic, trifluoroace
- Pharmaceutically acceptable salts of the compounds of formula (I) also include the salts with inorganic or organic bases, e.g., alkali or alkaline-earth metals, especially sodium, potassium, calcium, ammonium or magnesium hydroxides, carbonates or bicarbonates, and acyclic or cyclic amines, preferably methylamine, ethylamine, diethylamine, triethylamine, piperidine and the like.
- inorganic or organic bases e.g., alkali or alkaline-earth metals, especially sodium, potassium, calcium, ammonium or magnesium hydroxides, carbonates or bicarbonates, and acyclic or cyclic amines, preferably methylamine, ethylamine, diethylamine, triethylamine, piperidine and the like.
- the present invention provides compounds of formula (I) as defined above characterized in that
- R is hydrogen or fluorine
- n, m, R1 and R2 have the following meanings:
- R1 is a 6-membered heterocyclyl;
- R2 is a 3- or 6-membered cycloalkyl, 6-membered heterocyclyl, aryl or heteroaryl;
- n 1 and m is 0;
- R1 is aryl, optionally further substituted with one or more linear or branched (Ci-Ce)-alkyl;
- R2 is null
- n 2 or 3, and m is 0;
- R1 is a 6-membered heterocyclyl, aryl or heteroaryl, each of which optionally further substituted with one or more linear or branched (Ci-Ce)-alkyl;
- R2 is null, a 6-membered heterocyclyl or aryl
- n 2 or 3, and m is 1 ;
- R1 is a 6-membered heterocyclyl
- R2 is aryl
- the present invention provides compounds of formula (I) as defined above characterized in that
- R is hydrogen or fluorine
- n, m, R1 and R2 have the following meanings:
- n 0 and m is 0 or 1 ;
- R1 is a 6-membered heterocyclyl
- R2 is a 3- or 6-membered cycloalkyl, 6-membered heterocyclyl, aryl or heteroaryl;
- n 2 or 3, and m is 0;
- R1 is a 6-membered heterocyclyl, aryl or heteroaryl, each of which optionally further substituted with one or more linear or branched (Ci-Ce)-alkyl;
- R2 is null, a 6-membered heterocyclyl or aryl
- the present invention provides compounds of formula (I) as defined above characterized in that:
- R is hydrogen or fluorine
- n, m, R1 and R2 have the following meanings:
- n 0 and m is 0 or 1 ;
- R1 is a 6-membered heterocyclyl
- R2 is a 3- or 6-membered cycloalkyl, 6-membered heterocyclyl, aryl or heteroaryl;
- the present invention provides compounds of formula (I) as defined above characterized in that:
- R is hydrogen or fluorine
- n, m, R1 and R2 have the following meanings:
- n 0 and m is 0 or 1 ;
- R1 is a piperidine ring and R2 is a cyclohexyl ring;
- R1 is a piperidine ring and R2 is a pyridine ring;
- a process of the present invention comprises one of the following sequences of steps:
- Hal is halogen such as CI, Br, and I;
- Step f) esterifying the compound of formula (VII) obtained in step d) or e)
- T is a (Ci-Ce)-alkyl or an aryl-(Ci-Ce)-alkyl and Hal is as defined above;
- R1 and n are as defined above, and X is either R2-[CH2] m -, wherein R2 and m are as defined above, or a suitable nitrogen protective group, when R1 is a nitrogen containing heterocydyl;
- Step i) deprotecting the compound of formula (III), as defined above, so as to obtain either a compound of formula (I), as defined above, or
- R1 and n are as defined above;
- Step I) alkylating the resultant compound of formula (II), as defined above, with a suitable alkylating agent of formula (XIV)
- R1 and n are as defined above, and X is either R2-[CH2] m -, wherein R2 and m are as defined above, or a suitable nitrogen protective group, when R1 is a nitrogen containing heterocyclyl;
- Step n) performing a Diels-Alder reaction on the resultant com ound of formula (XVI): wherein R1 , n and X are as defined above;
- R1 , n and X are as defined above;
- n is as defined above, R1 is a nitrogen containing heterocyclyl and X is a suitable nitrogen protective group; Step i') deprotecting a compound of formula (XX) as defined above;
- Step o the compound resulting from aromatization of a compound of formula (XVII) is a compound of formula (XIX), i.e. when X is a labile nitrogen protective group, the following Step q is performed:
- the processes above described comprises converting a compound of formula (I) into a different compound of formula (I) by known chemical reactions; and/or, if desired, converting a compound of formula (I) into a pharmaceutically acceptable salt thereof or converting a salt into a free compound of formula (I).
- Such known chemical reactions for possible conversions of compounds into different compounds comprise for instance a reductive amination (Cv1).
- a compound of formula (X) can be obtained by halogenating 4-fluoro-2-methyl-phenylamine (XI) in a variety of ways and experimental conditions known in the art.
- this reaction is conducted in the presence of W-bromosuccinimide, N-iodosuccinimmide, N-chlorosuccinimide, bromine, iodine, hydrobromic acid/hydrogen peroxide, in a suitable solvent, such as acetonitrile, ⁇ , ⁇ -dimethylformamide, dioxane, dimethylsulfoxide, acetic acid or water, at a temperature ranging from about room temperature to reflux and for a period of time varying from about 1 h to about 96 h.
- a suitable solvent such as acetonitrile, ⁇ , ⁇ -dimethylformamide, dioxane, dimethylsulfoxide, acetic acid or water
- a compound of formula (IX) can be obtained by a two-steps reaction sequence from a compound of formula (X) in a variety of ways and experimental conditions known in the art.
- First step is preferably conducted in the presence of sodium nitrite/hydrochloric acid or ferf-butylnitrite in a suitable solvent, such as tetrahydrofuran, dimethoxyethane, dimethylsulfoxide, acetic acid or water, at a temperature ranging from about -20°C to room temperature and for a period of time varying from 10 min to about 24 h.
- a suitable solvent such as tetrahydrofuran, dimethoxyethane, dimethylsulfoxide, acetic acid or water
- Second step is preferably carried out in the presence of sodium, copper or potassium cyanide, often in the presence of an additive such as copper or potassium chloride, in a suitable solvent, such as tetrahydrofuran, dimethoxyethane, dimethylsulfoxide, acetic acid, toluene or water, at a temperature ranging from about -20°C to reflux and for a period of time ranging from about 10 min to about 96 h.
- a suitable solvent such as tetrahydrofuran, dimethoxyethane, dimethylsulfoxide, acetic acid, toluene or water
- step c) the hydrolysis of a compound of formula (IX) to a give a compound of formula (VIII) can be carried out in a variety of ways, according to conventional methods for transforming a cyano group to amide.
- this reaction is carried out in a suitable solvent such as, for instance, methanol, ethanol, butanol, 1 ,4- dioxane, toluene, water, or a mixture thereof, in the presence of a suitable acid or base, such as, for instance, sulfuric acid, methanesulfonic acid, hydrochloric acid, trifluoroacetic acid, sodium hydroxide, sodium carbonate, or a suitable reagent such as hydrogen peroxide, sodium perborate or indium(lll) salts in the presence of acetaldoxime.
- the reaction is carried out at a temperature ranging from room temperature to reflux and for a time varying from about 1 h to about 96 h.
- a compound of formula (VIII) can be transformed into a compound of formula (VII) according to conventional methods.
- the reaction is carried out in the presence of water by treatment with a base such as potassium or sodium carbonate, potassium or sodium hydroxide, in a suitable solvent such as, for instance, methanol or ethanol, at a temperature ranging from room temperature to reflux, for a time ranging from about 30 min to about 96 h.
- a base such as potassium or sodium carbonate, potassium or sodium hydroxide
- a suitable solvent such as, for instance, methanol or ethanol
- this reaction can be conducted in the presence of sodium nitrite/acetic acid, sulfuric acid, phosphoric acid, at a temperature ranging from room temperature to reflux and for a time varying from about 1 h to about 96 h.
- the halogenation of 4-fluoro-2-methyl-benzoic acid (XII) into a compound of formula (VII) can be carried out in a variety of ways, according to conventional methods for halogenation reactions.
- this reaction is carried out with tetrabutylammonium bromide and/or iodine in the presence of phenyliodine(lll) bis(trifluoracetate) or phenyliodo(lll) diacetate as halogen source in a suitable solvent such as, for instance, N,N- dimethylformamide or dichloroethane, at a temperature ranging from room temperature to reflux and for a time varying from about 1 h to about 48 h.
- the catalyst is usually a metal, most often a palladium derivative such as, for instance, palladium(ll) chloride or palladium(ll) acetate.
- a compound of formula (VII) can be transformed into a compound of formula (VI) according to conventional methods.
- the reaction is carried out in the presence of hydrochloric acid, sulfuric acid or acetic acid by using as a solvent methanol, ethanol, water, or a mixture thereof, at a temperature ranging from room temperature to reflux and for a time varying from about 1 h to about 96 h.
- this reaction can be conducted with alkyl iodide, bromide or toluensulfonate in the presence of a suitable base, such as sodium or potassium carbonate, and sodium, lithium or potassium hydroxide, at a temperature ranging from room temperature to reflux and for a time varying from about 1 h to about 96 h.
- a suitable base such as sodium or potassium carbonate, and sodium, lithium or potassium hydroxide
- step g) the transformation of a compound of formula (VI) into a compound of formula (V) can be carried out in a variety of ways, according to conventional methods for cyanation reactions.
- this reaction is carried out in the presence of copper(l) cyanide or potassium hexacyanoferrate(ll) as cyano source in a suitable solvent such as, for instance, methanol, ethanol, tetrahydrofuran, 1 ,4-dioxane, toluene, xylene, N-methyl-2- pyrrolidone, ⁇ , ⁇ -dimethylformamide, /V./V-dimethylacetamide or a mixture thereof, at a temperature ranging from room temperature to reflux and for a time varying from about 1 h to about 96 h.
- a suitable solvent such as, for instance, methanol, ethanol, tetrahydrofuran, 1 ,4-dioxane, toluene, xylene,
- a catalyst is usually a metal, most often a palladium derivative such as, for instance, tetrakis(triphenylphosphine)palladium(0), palladium(ll) chloride or palladium(ll) acetate in the presence of a suitable base such as, for instance, sodium, potassium or cesium carbonate or cesium fluoride.
- a suitable base such as, for instance, sodium, potassium or cesium carbonate or cesium fluoride.
- a compound of formula (IV) can be obtained by a two-steps reaction sequence from a compound of formula (V) in the presence of a compound of formula (XIII) in a variety of ways and experimental conditions known in the art.
- First step is preferably conducted in the presence of N-bromosuccinimide with a radical initiator such as benzoyl peroxide or azobisisobutyronitrile in a suitable solvent, such as carbon tetrachloride, chloroform, dichloromethane or methyl pivalate, at a temperature ranging from about room temperature to reflux and for a period of time varying from 10 min to about 24 h.
- a radical initiator such as benzoyl peroxide or azobisisobutyronitrile
- a suitable solvent such as carbon tetrachloride, chloroform, dichloromethane or methyl pivalate
- Second step can be conducted both under basic or acidic conditions, such as in the presence of sodium or potassium carbonate, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, triethylamine, diisopropylethylamine, pyridine or acetic acid, hydrochloric acid, in a suitable solvent, such as tetrahydrofuran, dimethoxyethane, 1 ,4-dioxane or toluene, at a temperature ranging from room temperature to reflux and for a period of time varying from 1 h to about 96 h.
- a suitable solvent such as tetrahydrofuran, dimethoxyethane, 1 ,4-dioxane or toluene
- step c' the hydrolysis of a compound of formula (IV) to give either a compound of formula (I) or a compound of formula (III), can be carried out in a variety of ways and experimental conditions. Preferably it is carried out in a way analogous to that reported for step c).
- a compound of formula (I) or a compound of formula (II) can be obtained by removing these protective groups under acidic conditions, preferably in the presence of an inorganic or organic acid such as hydrochloric, trifluoroacetic or methanesulphonic acid, boron tribromide or aluminium trichloride, in a suitable solvent, such as dichloromethane, dichloroethane, dioxane or a lower alcohol, such as methanol or ethanol, at a temperature ranging from room temperature to reflux.
- an inorganic or organic acid such as hydrochloric, trifluoroacetic or methanesulphonic acid, boron tribromide or aluminium trichloride
- a suitable solvent such as dichloromethane, dichloroethane, dioxane or a lower alcohol, such as methanol or ethanol
- X is a nitrogen protective group such as benzyloxycarbonyl and the like
- a compound of formula (I) or a compound of formula (II) can be obtained by removing these protective groups under reducing conditions, such as, for instance, in the presence of hydrogen and a hydrogenation catalyst in a suitable solvent, such as ethanol, methanol, ethyl acetate, or a mixture thereof.
- the catalyst is usually a metal, most often a palladium derivative such as, for instance, palladium on carbon, palladium hydroxide or palladium black.
- X is a nitrogen protective group such as methoxycarbonyl, ethoxycarbonyl, 9-fluorenylmethoxycarbonyl and the like
- a compound of formula (I) or a compound of formula (II) can be obtained by removing these protective groups under basic conditions such as, for instance, sodium, potassium or cesium carbonate, sodium, potassium or barium hydroxide, hydrazine, piperidine, morpholine or the like, in a suitable solvent, such as methanol, ethanol, water, ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide or the like, at a temperature ranging from room temperature to reflux.
- a suitable solvent such as methanol, ethanol, water, ⁇ , ⁇ -dimethylformamide, N,N- dimethylacetamide or the like
- step I) the reductive alkylation of a compound of formula (II), in the presence of a compound of formula (XIV), to give a compound of formula (I), can be conducted in a variety of ways, according to conventional methods for carrying out reductive amination.
- this reaction is carried out in a suitable solvent such as, for instance, methanol, ⁇ , ⁇ -dimethylformamide, dichloromethane, tetrahydrofuran, benzene, toluene, or a mixture thereof, in the presence of a suitable reducing agent such as, for instance, sodium borohydride, tetraalkylammonium borohydride, sodium cyano borohydride, sodium triacetoxyborohydride, tetramethylammonium triacetoxy borohydride and in the presence of an acid or basic catalyst, such as, for instance, acetic acid, trifluoroacetic acid, zinc chloride, zinc bromide, tin(IV) chloride, titanium(IV) chloride, boron trifluoride or triethylamine, diisopropylethylamine or pyridine, at a temperature ranging from about 0°C to reflux and for a time varying from about 1 h to about 96 h
- a compound of formula (XVI) can be obtained from furan-2-carbaldehyde (XV) through reductive amination in the presence of a compound of formula (XIII).
- this reaction is carried out in a suitable solvent such as, for instance, methanol, ⁇ , ⁇ -dimethylformamide, dichloromethane, tetrahydrofuran, benzene, toluene, or a mixture thereof, in the presence of a suitable reducing agent such as, for instance, sodium borohydride, tetraalkylammonium borohydride, sodium cyano borohydride, sodium triacetoxyborohydride or tetramethylammonium triacetoxy borohydride, and in the presence of an acid or basic catalyst, such as, for instance, acetic acid, trifluoroacetic acid, zinc chloride, zinc bromide, tin(IV) chloride, titanium(IV) chloride, boron trifluoride or
- step n) the Diels-Alder reaction, performed on a compound of formula (XVI) to give a compound of formula (XVII), can be conducted in a variety of ways, according to conventional methods for carrying out these reactions.
- this reaction is carried out in a suitable solvent such as, for instance, tetrahydrofuran, benzene, toluene or o-xylene, in the presence of maleic anhydride at a temperature ranging from about room temperature to reflux and for a time varying from about 1 h to about 96 h.
- step o) the transformation of a compound of formula (XVII) into either a compound of formula (XVIII) or a compound of formula (XIX), can be carried out in a variety of ways, according to conventional methods.
- this reaction is carried out in a suitable solvent such as, for instance, tetrahydrofuran, toluene or water, in the presence of hydrochloric acid, p-toluenesulfonic acid or phosphoric acid, at a temperature ranging from about room temperature to reflux and for a time varying from about 1 h to about 24 h.
- a suitable solvent such as, for instance, tetrahydrofuran, toluene or water
- hydrochloric acid, p-toluenesulfonic acid or phosphoric acid at a temperature ranging from about room temperature to reflux and for a time varying from about 1 h to about 24 h.
- a compound of formula (XVIII) can be reacted either to deliver a compound of formula (I) or a compound of formula (XX) in a variety of ways and experimental conditions, which are widely known in the art of condensation reactions.
- a compound of formula (XVIII) is reacted with ammonia or ammonia source such as ammonium salts, in the presence of an activating agent such as carbonyldiimidazole, benzotriazol-1- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, 2-(1 H-benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium tetrafluoroborate), (0-(7-azabenzotriazol-1-yl)-W,W,W',W'-tetramethyluronium hexafluorophosphate, dicyclohexyl carbodiimide, diisopropyl
- this reaction is carried out in a suitable solvent such as, for instance, ⁇ , ⁇ -dimethylformamide, N,/V-dimethylacetamide, tetrahydrofuran, dichloromethane or 1 ,4-dioxane, and in the presence of a proton scavenger such as, for example, pyridine, triethylamine or diisopropylethylamine, at a temperature ranging from room temperature to reflux, for a time ranging from about 30 min to about 96 h.
- a suitable solvent such as, for instance, ⁇ , ⁇ -dimethylformamide, N,/V-dimethylacetamide, tetrahydrofuran, dichloromethane or 1 ,4-dioxane
- a proton scavenger such as, for example, pyridine, triethylamine or diisopropylethylamine
- step i' the deprotection of a compound of formula (XX) to give a compound of formula (XXI), can be carried out in a variety of ways and experimental conditions. Preferably it is carried out in a way analogous to that reported for step i).
- step I' the reductive alkylation of a compound of formula (XXI), in the presence of a compound of formula (XIV), to give a compound of formula (I), can be carried out in a variety of ways and experimental conditions. Preferably it is carried out in a way analogous to that reported for step I).
- step q) the protection of compound of formula (XIX) to give a compound of formula (XVIII), where X is a suitable nitrogen protective group, may be carried out in a variety of ways and experimental conditions.
- the protective group is ferf-butoxycarbonyl
- the reaction may be carried out in the presence of di-ferf-butyl dicarbonate in a variety of solvents such as methanol, ethanol, acetonitrile, tetrahydrofuran or dichloromethane, in the presence of a base, such as pyridine, ⁇ , ⁇ -dimethylaminopyridine, triethylamine, diisopropylethylamine, sodium or potassium carbonate, at a temperature ranging from room temperature to reflux and for a time varying from about 1 h to about 96 h.
- a base such as pyridine, ⁇ , ⁇ -dimethylaminopyridine, triethylamine, diisopropylethylamine, sodium
- the reductive alkylation of a compound of formula (I) to give another compound of formula (I) may be carried out in a variety of ways and experimental conditions. Preferably, it is carried out in a way analogous to that reported for step I).
- Substituted isoindolinone derivatives can be prepared using standard procedures in organic synthesis as reported, for instance, in Smith, Michael - March's Advanced Organic Chemistry: reactions mechanisms and structure - 6 th Edition, Michael B. Smith and Jerry March, John Wiley & Sons Inc., New York (NY), 2007. It is known to the skilled person that transformation of a chemical function into another may require that one or more reactive centers in the compound containing this function have to be protected in order to avoid undesired side reactions. Protection of such reactive centers, and subsequent deprotection at the end of the synthetic transformations, can be accomplished following standard procedures described, for instance, in: Green, Theodora W. and Wuts, Peter G.M. - Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons Inc., New York (NY), 1999.
- a compound of formula (I) contains one or more asymmetric centers
- said compound can be separated into the single isomers by procedures known to those skilled in the art. Such procedures comprise standard chromatographic techniques, including chromatography using a chiral stationary phase, or crystallization. General methods for separation of compounds containing one or more asymmetric centers are reported, for instance, in Jacques, Jean; Collet, Andre; Wilen, Samuel H. - Enantiomers, Racemates, and Resolutions, John Wiley & Sons Inc., New York (NY), 1981.
- a compound of formula (I) can also be transformed into a pharmaceutically acceptable salt according to standard procedures that are known to those skilled in the art.
- a compound of formula (I) that is obtained as a salt can be transformed into the free base or the free acid according to standard procedures that are known to the skilled person.
- the starting materials of the process of the present invention i.e. 4-fluoro-2-methyl-phenylamine (XI), 4-fluoro-2- methyl-benzoic acid (XII), furan-2-carbaldehyde (XV) and compounds of formula (XIII) and (XIV) are either commercially available or can be prepared by using well-known methods.
- PARP-1 is a DNA damage-induced polymerase that catalyzes the cleavage of NAD+ into nicotinamide and ADP- ribose and then uses the latter to synthesize branched nucleic-acid like poly(ADP-ribose) polymers.
- ADP-ribosylated protein is PARP-1 itself, followed by histones.
- PARP-1 is responsible for 90% of this DNA damage-induced activity while the remaining 10% is due to PARP-2.
- the identification of compounds capable of binding several PARP proteins is carried out through a screening method including the steps of a) providing a reaction mixture containing:
- Rn is hydrogen or a methyl group
- B is (CH2) n -NH group wherein n is 2 to 6; m is 0 or 1 and X "" is a counterion, and
- both the PARP protein and the 5H-phenanthridin-6-one-derived probe of formula (IP) are pre-mixed, or the PARP protein and the test compound are pre-mixed.
- the PARP proteins are PARP-1 , PARP-2 and PARP-3.
- the term "PARP protein” encompasses full-length native proteins as well as fragments thereof. More preferably, Rn is hydrogen or methyl, m is 0 or 1 ; when m is 1 , n is 3 or 6, X "" is trifluoroacetate.
- the 5H-phenanthridin-6-one-derived probe (IP) was selected for its capability of binding to the PARP proteins, both encompassing full-length native proteins and fragments thereof.
- the polarization signal can be measured, e.g., by a plate reader such as the Saphire2 (Tecan).
- Data analysis was performed, e.g., by using the Dynafit software.
- Displacement data were also fitted, e.g., by using Excel spreadsheet (Microsoft Inc. Seattle, USA) to a four parameter logistic model (4PL), or Hill-Slope model.
- the assay was used to test compounds of the present invention.
- the displacement ability of the test compounds of formula (I) is in correlation with the compounds affinity for the NAD pocket of the enzyme.
- Specific probes of formula (IP) used in the assay are:
- a compound of formula (IP) as defined above can be prepared as described in WO 2010/133647.
- the assay is based on the use of a probe of formula (IP) that binds to the NAD binding pocket and takes advantage of the significant change in the polarization signal observed upon binding of the probe to PARP-1 , -2 and -3.
- the ability of the probe of formula (IP) to bind full-length PARP-1 , -2 and -3 has been previously reported (WO 2010/133647).
- the assay has been validated as described in WO 2010/133647.
- Affinity binding constants (Kd) and DC50S (the compound concentration at which the polarization signal is diminished by 50% compared to untreated controls) of the test compounds can be determined as explained in WO 2010/133647.
- cellular PAR immunoreactivity was assessed using the ArrayScan vTi instrument, with a Zeiss 10X 0.5 N.A. objective, and applying the Cytotoxicity. V3 algorithm (Cellomics/Thermo Fisher) with a XF100 filter. At least 10 fields, corresponding to at least 900 cells, were read for each well. IC50 Values represent the compound concentration at which cellular PAR signal is diminished by 50% compared with untreated controls.
- IC 50 Bottom + (Top-Bottom)/(1+10 A ((LogEC 50 -X))); is the logarithm of concentration, IC50 is the response; IC50 starts at bottom and goes to top with a sigmoid shape.
- compounds of formula (I) of the present invention inhibited PAR formation with IC50 values lower than 5 ⁇ , as depicted in Table 2.
- MDA-MB-436 breast cancer BRCA-1 mutated cells were grown at the density of 600 cells/cm 2 in RPMI medium supplemented with 10% Fetal Bovine Serum. 24 h later different doses of compounds were added starting from 10 ⁇ concentration in duplicates. Ten days later, cells were fixed and stained with crystal violet. Colonies were counted using Infrared Scanner (Odyssey Li-Cor). Anti proliferative IC50 was calculated using Prism.
- the pharmacokinetic profile and the oral bioavailability of the compounds have been investigated in the mouse (Balb,Nu/Nu, Harlan, Italy) in ad hoc pharmacokinetic studies.
- the compounds were formulated in 10% tween 80/dextrose for intravenous bolus administration while oral administrations were performed using the compounds formulated in 0.5% methylcellulose.
- a single administration at the dose of 10 mg/kg was given and three male animals for each route were used. All blood samples were taken from retro-orbital vein at 5 min, 30 min, 1 h, 3 h, 6 h, 24 h after intravenous administration and 15 min, 30 min, 1 h, 3 h, 6 h, 24 h after oral administration.
- Plasma samples were prepared by plasma proteins precipitation adding 200 ⁇ .
- AUC area under the plasma concentration vs. time curve up to the last detectable concentration
- Vdss volume of distribution at steady state
- mice athymic Nu/Nu male mice, from Harlan (Italy), were maintained in agreement with the European Communities Council Directive no. 86/609/EEC concerning the protection of animals used for experimental or other scientific purposes, in cages with paper filter cover, food and bedding sterilized and acidified water. Fragments of Capan-1 human pancreatic cancer tumors were implanted subcutaneously. Mice bearing a palpable tumor (100-200 mm 3 ) were selected and randomized into control and treated groups. Each group included seven animals. The treatment started one day after randomization. Compound of formula (I) was administered by oral route as a methocel suspension at the indicated doses and times.
- Tumor dimension was measured regularly by calipers during the experiments and tumor mass was calculated as described in Simeoni M. et al., Cancer Res 64, 1094-1101 (2004).
- Representative compounds of formula (I) were evaluated for their anti-tumor activity on Capan-1 BRCA-2 mutated mouse model in combination with temozolomide.
- Compounds of formula (I) and temozolomide were both administered by oral route. Tumor growth was assessed by caliper. The two diameters were recorded and the tumor weight was calculated according to the following formula: length (mm) x width 2 / 2.
- the effect of the antitumor treatment was evaluated as the delay in the onset of an exponential growth of the tumor (see for references Anticancer drugs 7:437-60, 1996). This delay (T-C value) was defined as the difference of time (in days) required for the treatment group (T) and the control group (C) tumors to reach a predetermined size (1 g).
- Toxicity was evaluated on the basis of body weight reduction and animal survival rate.
- the T-C observed when Compounds of formula (I) were combined with temozolomide was superior to the one expected by the simple addition of T-C obtained by the single treatments, thus indicating strong synergism.
- the present invention provides compounds of formula (I) useful in therapy.
- Compounds of formula (I) of the present invention suitable for administration to a mammal, e.g., to humans, can be administered by the usual routes and the dosage level depends upon the age, weight, conditions of the patient and administration route.
- a suitable dosage adopted for oral administration of a compound of formula (I) may range from about 1 to about 1000 mg per dose, from 1 to 5 times daily.
- the compounds of the invention can be administered in a variety of dosage forms, e.g., orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or suspensions; rectally in the form of suppositories; parenterally, e.g., intramuscularly, or through intravenous and/or intrathecal and/or intraspinal injection or infusion.
- the present invention also includes pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable excipient, which may be a carrier or a diluent.
- a pharmaceutically acceptable excipient which may be a carrier or a diluent.
- compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a suitable pharmaceutical form.
- the solid oral forms may contain, together with the active compound, diluents, e.g., lactose, dextrose, saccharose, sucrose, cellulose, corn starch or potato starch; lubricants, e.g., silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g., starches, arabic gum, gelatine methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents, e.g., starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, polysorbates, laurylsulphates; and, in general, nontoxic and pharmacologically inactive substances used in pharmaceutical formulations
- liquid dispersions for oral administration may be, e.g., syrups, emulsions and suspensions.
- the syrups may contain, as carrier, saccharose or saccharose with glycerine and/or mannitol and sorbitol.
- the suspensions and the emulsions may contain, as examples of carriers, natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
- the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., sterile water, olive oil, ethyl oleate, glycols, such as propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride.
- the solutions for intravenous injections or infusions may contain, as a carrier, sterile water or preferably they may be in the form of sterile, aqueous, isotonic, saline solutions or they may contain propylene glycol as a carrier.
- the suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
- a pharmaceutically acceptable carrier e.g., cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
- FCS Fretal Calf Serum
- FBS Fetal Bovine Serum
- CDCI3 deuterated chloroform
- Triethylamine (0.41 mL, 2.9 mmol) and 3-morpholin-4-yl-propylamine (XIII) (140 mg, 0.97 mmol) were added and the reaction mixture was stirred at 90°C for 3 h. Crude was diluted with dichloromethane and washed with 15% ammonium hydroxide. The organic phase was dried over Na2S04, filtered and evaporated.
- the resultant dark mixture was cooled to room temperature, diluted with methyl-ferf-butylether (200 mL) and treated with a solution of sodium metabisulfite (250 g) in water (500 mL) under efficient stirring. Then, this yellow colored mixture was acidified by slowly adding cone, hydrochloric acid (130 mL). The aqueous layer was separated and extracted twice with methyl-ferf-butylether (mL100 x 2). The combined organic extracts were treated with a solution of sodium hydroxide pellets (80 g) in water (300 mL) under stirring.
- the thick reaction mixture was diluted with methyl-ferf-butylether (100 mL) and washed with water (600 mL); the aqueous layer was separated and extracted twice with methyl-ferf-butylether (70 mL x 2). The combined organic extracts were washed with brine (50 mL), dried over Na2S04 and concentrated under reduced pressure to a solid residue. This material was purified by chromatography (eluant n-hexane/ethyl acetate 9:1), affording 26.2 g (81 %) of product as colorless oil.
- Method B a solution of 2-(1-ferf-butoxycarbonyl-piperidin-4-yl)-2,3-dihydro-1 H-isoindole-4-carboxylic acid (XVIII) (5.5 g, 15.3 mmol) and carbonyldiimidazole (3.7 g , 22.8 mmol) in dry tetrahydrofuran (80 mL) was stirred at room temperature for 4 h. Then concentrated aqueous ammonia (25 mL) was added and the reaction mixture was left at room temperature until the disappearance of the starting material (3 h). The solvent was evaporated under reduced pressure and the resulting crude primary amide (1.1 g, 20%) was employed without any further purification.
- XVIII 2-(1-ferf-butoxycarbonyl-piperidin-4-yl)-2,3-dihydro-1 H-isoindole-4-carboxylic acid
- XVIII 2-(1-ferf-butoxycarbony
- Method B to a solution of 2-piperidin-4-yl-2,3-dihydro-1 H-isoindole-4-carboxylic acid amide hydrochloride (4.4 g, 14.8 mmol) and cyclohexanone (2.2 g, 22.45 mmol) in N,N-dimethylformamide (100 mL), glacial acetic acid (4.5 mL) and tetramethylammonium triacetoxyborohydride (11.8 g, 44.85 mmol) were added. The resulting solution was allowed to stir overnight at room temperature.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
Priority Applications (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EA201590820A EA028506B1 (ru) | 2012-10-26 | 2013-10-23 | Производные 4-карбоксамидо-изоиндолинона в качестве селективных ингибиторов parp-1, способ их получения и применение |
ES13780358T ES2813530T3 (es) | 2012-10-26 | 2013-10-23 | Derivados de 4-carboxamido-isoindolinona como inhibidores selectivos de PARP-1 |
MX2015005245A MX367425B (es) | 2012-10-26 | 2013-10-23 | Derivados de 4-carboxamido-isoindolinona como inhibidores selectivos de parp-1. |
EP13780358.1A EP2912032B1 (en) | 2012-10-26 | 2013-10-23 | 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitors |
CN201380055668.XA CN104768948B (zh) | 2012-10-26 | 2013-10-23 | 作为选择性parp-1抑制剂的4-甲酰氨基-异二氢吲哚酮衍生物 |
JP2015538431A JP6314147B2 (ja) | 2012-10-26 | 2013-10-23 | 選択的parp−1阻害剤としての4−カルボキサミド−イソインドリノン誘導体 |
KR1020157013730A KR102221199B1 (ko) | 2012-10-26 | 2013-10-23 | 선택적 parp-1 억제제로서의 4-카복스아미도-이소인돌리논 유도체 |
DK13780358.1T DK2912032T3 (da) | 2012-10-26 | 2013-10-23 | 4-carboxamido-isoindolinonderivater som selektive parp-1-hæmmere |
BR112015009130-0A BR112015009130B1 (pt) | 2012-10-26 | 2013-10-23 | Compostos derivados de 4-carboxamido-isoindolinona, processo de preparação destes, método in vitro para inibir seletivamente a atividade de proteína parp-1, composição farmacêutica e uso dos referidos compostos |
CA2889581A CA2889581C (en) | 2012-10-26 | 2013-10-23 | 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitors |
US14/438,410 US10385018B2 (en) | 2012-10-26 | 2013-10-23 | 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitors |
AU2013336725A AU2013336725B2 (en) | 2012-10-26 | 2013-10-23 | 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitors |
PL13780358T PL2912032T3 (pl) | 2012-10-26 | 2013-10-23 | Pochodne 4-karboksyamido-izoindolinonu jako selektywne inhibitory parp-1 |
SI201331777T SI2912032T1 (sl) | 2012-10-26 | 2013-10-23 | Derivati 4-karboksamido-izoindolinona kot selektivni zaviralci PARP-1 |
HK16100120.5A HK1212331A1 (en) | 2012-10-26 | 2016-01-07 | 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitors parp-1 4-- |
US16/460,438 US10800739B2 (en) | 2012-10-26 | 2019-07-02 | 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitors |
US17/018,504 US11420940B2 (en) | 2012-10-26 | 2020-09-11 | 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitors |
US17/863,941 US11773064B2 (en) | 2012-10-26 | 2022-07-13 | 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP12190130.0 | 2012-10-26 | ||
EP12190130 | 2012-10-26 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/438,410 A-371-Of-International US10385018B2 (en) | 2012-10-26 | 2013-10-23 | 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitors |
US16/460,438 Division US10800739B2 (en) | 2012-10-26 | 2019-07-02 | 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitors |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014064149A1 true WO2014064149A1 (en) | 2014-05-01 |
Family
ID=47115518
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2013/072165 WO2014064149A1 (en) | 2012-10-26 | 2013-10-23 | 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitors |
Country Status (19)
Country | Link |
---|---|
US (4) | US10385018B2 (es) |
EP (1) | EP2912032B1 (es) |
JP (1) | JP6314147B2 (es) |
KR (1) | KR102221199B1 (es) |
CN (1) | CN104768948B (es) |
AU (1) | AU2013336725B2 (es) |
BR (1) | BR112015009130B1 (es) |
CA (1) | CA2889581C (es) |
CL (1) | CL2015001020A1 (es) |
DK (1) | DK2912032T3 (es) |
EA (1) | EA028506B1 (es) |
ES (1) | ES2813530T3 (es) |
HK (1) | HK1212331A1 (es) |
HU (1) | HUE051078T2 (es) |
MX (1) | MX367425B (es) |
PL (1) | PL2912032T3 (es) |
PT (1) | PT2912032T (es) |
SI (1) | SI2912032T1 (es) |
WO (1) | WO2014064149A1 (es) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111100116A (zh) * | 2019-11-14 | 2020-05-05 | 南京大学 | 一类新型的含甲基吲哚的以吡唑啉为骨架的苯胺衍生物的制备方法及应用 |
US20220363636A1 (en) * | 2012-10-26 | 2022-11-17 | Nerviano Medical Sciences S.R.L. | 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitors |
US11591331B2 (en) | 2021-04-19 | 2023-02-28 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
US11795173B1 (en) | 2022-04-28 | 2023-10-24 | Xinthera, Inc. | Substituted pyridines as PARP1 inhibitors |
US11802128B2 (en) | 2021-10-01 | 2023-10-31 | Xinthera, Inc. | Azetidine and pyrrolidine PARP1 inhibitors and uses thereof |
WO2023242302A1 (en) | 2022-06-15 | 2023-12-21 | Astrazeneca Ab | Combination therapy for treating cancer |
US11939329B2 (en) | 2022-01-21 | 2024-03-26 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111205263A (zh) * | 2020-04-22 | 2020-05-29 | 北京鑫开元医药科技有限公司 | 一种双环醇的制备方法及用途 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011006794A1 (en) * | 2009-07-14 | 2011-01-20 | Nerviano Medical Sciences S.R.L. | 3-oxo-2, 3-dihydro-lh-isoindole-4-carboxamides as parp inhibitors |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7232842B2 (en) | 2003-01-10 | 2007-06-19 | Board Of Trustees Of The Leland Stanford Junior University | Kinase inhibitors and associated pharmaceutical compositions and methods of use |
WO2007047646A2 (en) | 2005-10-14 | 2007-04-26 | Janssen Pharmaceutica, N.V. | Substituted dihydro-isoindolones useful in treating kinase disorders |
JP4929834B2 (ja) * | 2006-05-18 | 2012-05-09 | 富士通セミコンダクター株式会社 | ラッチ回路 |
US8143284B2 (en) | 2006-10-05 | 2012-03-27 | Abbott Laboratories | Poly(ADP-ribose)polymerase inhibitors |
CA2623257A1 (en) * | 2008-02-29 | 2009-08-29 | Scanimetrics Inc. | Method and apparatus for interrogating an electronic component |
TWI499418B (zh) | 2009-05-21 | 2015-09-11 | Nerviano Medical Sciences Srl | 異喹啉-1(2h)-酮衍生物 |
JP5744019B2 (ja) * | 2009-07-14 | 2015-07-01 | ネルビアーノ・メデイカル・サイエンシーズ・エツセ・エルレ・エルレ | 選択的parp−1阻害を有する3−オキソ−2,3−ジヒドロ−1h−イソインドール−4−カルボキサミド |
US10385018B2 (en) * | 2012-10-26 | 2019-08-20 | Nerviano Medical Sciences S.R.L. | 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitors |
-
2013
- 2013-10-23 US US14/438,410 patent/US10385018B2/en active Active
- 2013-10-23 SI SI201331777T patent/SI2912032T1/sl unknown
- 2013-10-23 AU AU2013336725A patent/AU2013336725B2/en active Active
- 2013-10-23 PT PT137803581T patent/PT2912032T/pt unknown
- 2013-10-23 PL PL13780358T patent/PL2912032T3/pl unknown
- 2013-10-23 EP EP13780358.1A patent/EP2912032B1/en active Active
- 2013-10-23 ES ES13780358T patent/ES2813530T3/es active Active
- 2013-10-23 KR KR1020157013730A patent/KR102221199B1/ko active IP Right Grant
- 2013-10-23 HU HUE13780358A patent/HUE051078T2/hu unknown
- 2013-10-23 BR BR112015009130-0A patent/BR112015009130B1/pt active IP Right Grant
- 2013-10-23 CN CN201380055668.XA patent/CN104768948B/zh active Active
- 2013-10-23 EA EA201590820A patent/EA028506B1/ru not_active IP Right Cessation
- 2013-10-23 WO PCT/EP2013/072165 patent/WO2014064149A1/en active Application Filing
- 2013-10-23 DK DK13780358.1T patent/DK2912032T3/da active
- 2013-10-23 CA CA2889581A patent/CA2889581C/en active Active
- 2013-10-23 JP JP2015538431A patent/JP6314147B2/ja active Active
- 2013-10-23 MX MX2015005245A patent/MX367425B/es active IP Right Grant
-
2015
- 2015-04-22 CL CL2015001020A patent/CL2015001020A1/es unknown
-
2016
- 2016-01-07 HK HK16100120.5A patent/HK1212331A1/xx unknown
-
2019
- 2019-07-02 US US16/460,438 patent/US10800739B2/en active Active
-
2020
- 2020-09-11 US US17/018,504 patent/US11420940B2/en active Active
-
2022
- 2022-07-13 US US17/863,941 patent/US11773064B2/en active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011006794A1 (en) * | 2009-07-14 | 2011-01-20 | Nerviano Medical Sciences S.R.L. | 3-oxo-2, 3-dihydro-lh-isoindole-4-carboxamides as parp inhibitors |
Non-Patent Citations (1)
Title |
---|
GANDHI V B ET AL: "Discovery and SAR of substituted 3-oxoisoindoline-4-carboxamides as potent inhibitors of poly(ADP-ribose) polymerase (PARP) for the treatment of cancer", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, GB, vol. 20, no. 3, 1 February 2010 (2010-02-01), pages 1023 - 1026, XP026861859, ISSN: 0960-894X, [retrieved on 20100119] * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20220363636A1 (en) * | 2012-10-26 | 2022-11-17 | Nerviano Medical Sciences S.R.L. | 4-carboxamido-isoindolinone derivatives as selective parp-1 inhibitors |
US11773064B2 (en) * | 2012-10-26 | 2023-10-03 | Nerviano Medical Sciences S.R.L. | 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitors |
CN111100116A (zh) * | 2019-11-14 | 2020-05-05 | 南京大学 | 一类新型的含甲基吲哚的以吡唑啉为骨架的苯胺衍生物的制备方法及应用 |
US11591331B2 (en) | 2021-04-19 | 2023-02-28 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
US11802128B2 (en) | 2021-10-01 | 2023-10-31 | Xinthera, Inc. | Azetidine and pyrrolidine PARP1 inhibitors and uses thereof |
US11939329B2 (en) | 2022-01-21 | 2024-03-26 | Xinthera, Inc. | PARP1 inhibitors and uses thereof |
US11795173B1 (en) | 2022-04-28 | 2023-10-24 | Xinthera, Inc. | Substituted pyridines as PARP1 inhibitors |
US12006322B2 (en) | 2022-04-28 | 2024-06-11 | Xin Thera, Inc. | Substituted pyridines as PARP1 inhibitors |
WO2023242302A1 (en) | 2022-06-15 | 2023-12-21 | Astrazeneca Ab | Combination therapy for treating cancer |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11773064B2 (en) | 4-carboxamido-isoindolinone derivatives as selective PARP-1 inhibitors | |
US8877944B2 (en) | 3-oxo-2,3-dihydro-1H-isoindole-4-carboxamides as PARP inhibitors | |
US8592416B2 (en) | Isoquinolin-1 (2H)-one derivatives as PARP-1 inhibitors | |
US8765972B2 (en) | 3-oxo-2,3-dihydro-1H-isoindole-4-carboxamides with selective PARP-1 inhibition | |
US9073893B2 (en) | 3-Oxo-2,3-dihydro-1H-indazole-4-carboxamide derivatives as PARP-1 inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 13780358 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2889581 Country of ref document: CA Ref document number: 2015538431 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 14438410 Country of ref document: US Ref document number: MX/A/2015/005245 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112015009130 Country of ref document: BR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2013780358 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 20157013730 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 201590820 Country of ref document: EA |
|
ENP | Entry into the national phase |
Ref document number: 2013336725 Country of ref document: AU Date of ref document: 20131023 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 112015009130 Country of ref document: BR Kind code of ref document: A2 Effective date: 20150422 |